Women, HIV and PMTCT Unit 11 HIV Care and ART: A Course for Physicians Learning Objectives Part 1: Women and HIV List women’s risk factors for HIV and identify strategies to reduce risk Identify gynecological conditions associated with HIV in women Describe gender differences in ARV treatment 2 Learning Objectives Part 2: HIV and PMTCT List the factors that affect HIV transmission during pregnancy, labor, delivery and breastfeeding Identify how to prescribe ART appropriately for pregnant women and exposed newborns Describe labor, delivery and postpartum care for HIV+ women and their infants 3 Part 1: Women and HIV Global Facts Of 40 million people living with HIV/AIDS worldwide, 17.5 are women (2005) 77% of all women living with HIV are in subSaharan Africa (2005) Among HIV positive adults, women account for 57% in sub-Saharan Africa, 26% in southeast Asia, 27% in Europe, and 25% in the US (2005) 5 Source: UNAIDS/WHO 2004 6 Source: UNAIDS/WHO 2004 7 Vulnerability Factors Biological Economic Social Cultural “Women are most vulnerable to HIV infection, given the social and economic disadvantages they face in their day to day lives.” • Dr. Nafis Sadik, Executive Director of the United Nations Population Fund 8 Gender Differences Viral load Disease progression Drug pharmocokinetics Lipodystrophy Lactic acidosis Contraceptives Adherence Gynecological issues 9 Viral Load and Disease Progression Women may have lower viral loads than men in early disease Low viral load may NOT truly reflect low risk for progression Women and men progress at similar rates Gender is not significantly associated with time to AIDS or survival time 10 Drug Pharmacokinetics Differences in weight and body mass Fat to muscle distribution Concentration of enzymes needed for drug metabolism is different Hormonal effects Pregnancy Hormonal replacement therapy Oral contraceptives 11 Lipodystrophy Fat accumulation more common in women; fat depletion more common in men Accumulation and depletion in different body areas of same person occurs equally in men and women Lipid abnormalities: triglyceride and cholesterol level elevations more common in men 12 Lactic Acidosis The FDA has received 60 reports of lactic acidosis associated with dual nucleosides, with 55% mortality 83% in women; 50% >175lbs Presented with nonspecific symptoms Link between mitochondrial dysfunction and lactic acidosis? Occurs in women with high CD4 13 Contraception and ART Because Efavirenz is contraindicated during pregnancy, dual methods of contraception are highly recommended for sexually active EFV users: barriers plus Progestins (Depo-Provera) IUCD Nelfinavir, Nevirapine and Ritonavir Associated with decreased levels of ethinyl estradiol, resulting in decreased contraceptive effectiveness Do not combine 14 Contraception and ART (2) NNRTIs and PIs interfere with blood levels of combination oral contraceptives Additional barrier methods are recommended to prevent pregnancy and transmission of HIV and STIs 15 Women and Adherence Adherence issues are more complicated for women who need special attention and support: Often don’t disclose HIV status due to stigma May feel isolated Caregivers Challenges in accessing and maintaining care include child care, transportation, inexperienced providers, etc. 16 Optimal Adherence for Women Evaluate for mental health, substance abuse and other “adherence interruptus” problems Assess HAART readiness Develop a mutually agreeable HAART regimen specific to her lifestyle Prepare for side effects Encourage atmosphere of communication and trust Be accessible and available 17 Gynecological Issues Conditions causing inflammation or infection increase the likelihood a woman will acquire or transmit HIV Bacterial vaginosis Cervicitis Herpes ulcers Genital warts Condyloma Recurrent candidiasis Prevalent in 25-30% of women with HIV Risk increases 20-fold with CD4<100 HPV genital warts associated with increased incidence of cervical cancer 18 Care for HIV+ Women Regular gynecologic care Pap smear (yearly and as needed) Detects cervical dysplasia (human papillomavirus) and sexually transmitted diseases Untreated HIV disease is associated with increased risk of cervical abnormalities Reproductive counseling 19 Care for HIV+ Women Desiring Pregnancy Give accurate information on MTCT Maintain good health and nutrition status Provide ARVs to eligible women, or consider delaying until after the first trimester 20 Ongoing Care for Women with HIV Infection Psychological support Social support Medical support Nutritional advice Prophylaxis of TB, PCP, malaria, other infections Physical examination that includes gynecologic exam and cervical smears 21 Treatment Guidelines for Women Guidelines are the same for women and men Women and men have similar responses to initial ART Because many women weigh less than men, it is important to monitor for toxicity 22 Part 2: HIV, Pregnancy and Preventing Maternal to Child Transmission Introduction HIV is a family infection Mothers and fathers have an impact on transmission of HIV to the baby There is increased chance of transmission to the baby when a woman becomes infected with HIV when she is pregnant or breastfeeding Partners should have safer sex throughout pregnancy and while breastfeeding 24 Pregnancy Outcome: Goals Uncomplicated pregnancy Healthy, uninfected infant Healthy mother who has not compromised her future options for HIV therapy 25 HIV and Pregnancy Pregnancy does not accelerate the progression of HIV disease to AIDS Patients with AIDS are more likely to suffer from pregnancy-related complications 26 Effect of Advanced HIV on Pregnancy Decreased fertility Spontaneous abortion Infections (opportunistic, GU, postpartum, postsurgical) Preterm labor Premature rupture of membranes Low birth weight babies Stillbirths 27 Current Status of Mother-to-Child Transmission Estimates of HIV transmission rates from women to children are about 20-40% MTCT is by far the largest source of HIV infection in children under 15 28 Estimated Risk of MTCT (Adapted from De Cock KM et al, 2000) Timing Transmission Rate Without Any Interventions During pregnancy 5-10% During labor and delivery 10-15% During breastfeeding 5-20% Overall without breastfeeding 15-25% Overall with breastfeeding to six months 20-35% Overall with breastfeeding to 18-24 months 30-45% Note: Rates vary because of differences in population characteristics such as maternal CD4+ cell counts, RNA viral load and duration of breastfeeding. “HIV transmission through breastfeeding: A review of available evidence.” Marie Louise Newell; endorsed by UNICEF, UNFPA, WHO, UNAIDS. 2004 (adapted from De Cock KM et al., 2000). 29 Of 100 Babies Born to HIV- Infected Mothers Not on Treatment… 11 infected during breastfeeding 17 infected during birth 67 not infected* 5 infected in utero *without treatment for parents, most will be orphaned 30 Factors Influencing MTCT Viral Load The higher the viral load, the higher the risk of MTCT Lower risk through: Use of ART during pregnancy and postpartum to mother and newborn Adequate nutrition, particularly vitamin A 31 Factors Influencing MTCT (2) Maternal factors increasing risk: Viral or parasitic placental infection (especially malaria) Becoming infected with HIV during pregnancy Severe immune deficiency Advanced clinical and immunological state Maternal malnutrition 32 Factors Influencing MTCT (3) Labor and delivery factors increasing risk: Prolonged rupture of membranes (>4 hours) Injury to birth canal during child birth Antepartum procedures Acute chorioamnionitis Invasive fetal monitoring Instrumental delivery Mixing of maternal and fetal body fluids Delayed infant cleaning and eye care Routine infant airway suctioning 33 Factors Influencing MTCT (4) Fetal Conditions increasing risk: Premature delivery Low birth weight Immature immune status First infant in a multiple birth Oral diseases 34 National Strategies for PMTCT Primary prevention of HIV in childbearing women Prevention of unintended pregnancy in HIVpositive women Prevention of transmission from HIV+ women to their infants Treatment, care and support of women infected with HIV, their infants and their families 35 Antenatal Care Primary prevention during pregnancy Education about safer sex with use of condoms for mother and father Early treatment of STIs Safer sex during pregnancy and lactation Offer VCT to all pregnant women Antenatal visits are vital opportunities for PMTCT for both HIV-positive and HIV-negative women 36 Initial Examination All pregnant women Syphilis test Hgb HIV counseling and consent HIV test (rapid, if available) Rule out active TB If HIV positive: Baseline TLC CD4 and CD8 counts CD4/CD8 ratio and all other baseline tests (CBC, LFT, etc.) Viral load screening 37 Initial Examination (2) Additionally, if HIV+: Duration of known HIV+ status Past history of HIV-related illness and HAART WHO Staging Status of other children, partner, and partner disclosure and referral Any medications taken for HIV-related illness since beginning of pregnancy 38 Assess Maternal Psychosocial Status Generalities and pains Headaches Anxiety General malaise Depression Palpitations Insomnia Irritability 39 Care of the HIV+ Pregnant Woman Treatment: OIs STI UTI Vaginal candidiasis ARV Vitamin supplements Prophylaxis: Anemia Tetanus (Toxic-TT) Vitamin deficiency Malaria Pneumonia (PCP) TB 40 PMTCT Clinical Scenarios Six possible clinical scenarios of a pregnant woman: On ART and become pregnant Pregnant and eligible for ART Pregnant and not requiring ART Pregnant and presenting after 34 weeks Pregnant and presenting in labor Woman and child presenting postpartum 41 Scenario 1: On ART and Become Pregnant Woman on efavirenz Counsel about potential teratogenicity Stop EFV and start NVP if in first trimester Women on ZDV/DDI/LPV/r Continue treatment Full blood count monthly Monitor blood glucose levels as appropriate Woman on D4T/3TC/nevirapine Continue treatment or change D4T to ZDV ALT monthly & when indicated Monthly full blood count if on ZDV 42 Scenario 2: Pregnant and Eligible for ART Begin first line therapy: ZDV 300 mg bid or D4T 40 mg every 12 hours (or 30 mg q 12 hours if <60 kg) and 3TC 150 mg q12 hrs and NVP 200 mg qd for 2 weeks, then 200 mg q12 hrs If unable to use NVP, PI options include NFV, LPV/r or SQV/r ALT q 2 weeks for 1 month, then q month and then as indicated 43 Scenario 3: Pregnant and Not Requiring ART Early stage HIV (WHO Stage I or II disease with CD4 >200) Follow the national PMTCT guidelines 44 Scenario 4: Pregnant Woman Presenting After 34 Weeks Defer ART Provide PMTCT Review need for ART after delivery 45 Scenario 5: Pregnant Woman Presenting in Labor NVP single dose given at the onset of labor and post delivery to the infant or AZT & 3TC to the mother during labor and infant post delivery or IV AZT (alone or with NVP) to the mother and AZT syrup to the infant post partum for six weeks, in addition to a single dose of Nevirapine 46 Scenario 6: Woman and Child Presenting Post Partum Initiate 6 week neonatal AZT protocol, preferably within 6-12 hours of delivery or Single dose Nevirapine plus AZT for the infant for four weeks Mother should be evaluated for HAART 47 Four Options for PMTCT (Scenarios 3-5) Nevirapine monotherapy to mother and infant Zidovudine monotherapy to mother and infant Nevirapine + zidovudine to mother and infant Zidovudine + lamivudine to mother and infant 48 National PMTCT Drug Regimen to the Mother Antepartum 1) Nevirapine 2) Zidovudine 300 mg po BID from 36 weeks onwards Regimen to the Baby Intrapartum 200 mg po at onset of labor ^^2 mg/kg po single dose within 72 hours postpartum x1 300 mg po every 3 hours 4 mg/kg BID po for 7 days beginning at 8-12 hours postpartum 600 mg at onset of labor then 300 mg every 3 hours** Same as above 49 3) Combination of zidovudine and nevirapine as above National PMTCT (2) Drug 4) Zidovudine & Lamivudine Regimen to the Mother Regimen to the Baby Antepartum Intrapartum 300 mg po BID from 36 weeks onwards & 600 mg po at onset of labor, then 300 po mg every 3 hours & 4 mg/kg po BID for 7 days 150 mg po BID from 36 weeks onwards 150 mg at onset of labor then 150 mg every 12 hours 2 mg/kg po BID for 7 days, both beginning within 72 hours postpartum & 50 Nevirapine Reduces Transmission During Birth by 41% No intervention Single dose NVP to mother and baby* 17 infected during birth 5 infected in utero 11 infected during BF 67 not infected 10 infected during birth* 5 infected in utero 11 infected during BF 74 not infected Source: Adapted from Lancet 2003;362:859-68 51 Intrapartum Nevirapine Single dose (200 mg) to mother in labor Rapidly absorbed May rapidly reduce mother’s viral load in blood and birth canal NVP crosses placenta and enters baby NVP provides prophylaxis to the baby during the birth No side effects with single dose (hepatotoxicity or rash) 52 Postpartum Nevirapine Single dose (2 mg/kg, 0.2 ml/kg) to newborn 4872 hours after birth Maintains therapeutic levels in baby’s bloodstream for the first week of life Acts as post-exposure prophylaxis No side effects with single dose If mother received her dose of NVP less than 2 hours prior to delivery, give one dose of NVP to baby at birth and a second dose at 48-72 hrs 53 Antiretroviral Resistance with Nevirapine Following single-dose NVP, resistance mutations present 6 weeks postpartum in 20-30% of women 46% of infants No longer detectable 12 months postpartum (due to reappearance of wild type virus). Mutant virus archived indefinitely 54 Antiretroviral Resistance with Nevirapine (2) Following single-dose intrapartum NVP, some mothers have a decreased response to NVPbased HAART Problem is the greatest if HAART is given within a few months of single-dose NVP Risk of NVP resistance appears greatly increased with second maternal dose 55 Postpartum NVP levels (HPLC) (NVP IC50 =3-30 ng/ml) Undetectable 5 10 15 20 Days post dose Source: G. Jourdain et al. 11th CROI, San Francisco, CA, 2004. Abstract 41LB 56 3 and 6 Month Responders (50 copies/mL) Copyright © 1998 Massachusetts Medical Society. All rights reserved. Source: Jordain et al., NEJM 2004; 351: 229-240 57 Addition of Short-course ZDV/3TC to Single-dose NVP for MTCT Prophylaxis Interim analysis of 61 mothers (target = 300) with 6 weeks of resistance data No NNRTI resistance at baseline in any group NVP resistance at Week 6 NVP alone 60% NVP plus combivir 10% • NVP + ZDV/3TC x 4 d • NVP + ZDV/3TC x 7 d 12.0% 10% No 184V or NRTI resistance detected McIntyre J, et al. XV IAC, Bangkok 2004, #LBOrB09 58 ARV Therapy: HAART Results in the lowest risk of transmission to the infant (<2%) Reduces the risk of the mother developing resistance, thereby preserving her future treatment options Improves maternal immune status, improving survival Risks to infant appear to be minimal for most regimens 59 Safety of NRTI Drugs in Pregnancy Balance between PMTCT and therapy for mother vs. potential teratogenicity, toxicity, and drug resistance Human pregnancy data only for AZT, 3TC, ddI, d4T No increase in birth defects have been observed NRTIs and mitochondrial toxicity: symptomatic lactic acidosis and hepatic steatosis may have a female preponderance 60 Safety of NRTI Drugs in Pregnancy (2) Fatal lactic acidosis described in pregnant women receiving ddI/d4T along with other ART ddI/d4T SHOULD NOT BE USED IN PREGNANT WOMEN 61 Safety of NNRTIs in Pregnancy Single dose nevirapine has not been associated with adverse side effects in women and children Nevirapine resistance risk as above Nevirapine elimination may be accelerated in infants whose mother received chronic nevirapine as part of ART. Significance? No human pregnancy data on long term use of NNRTIs 62 Safety of NNRTIs in Pregnancy (2) Efavirenz causes birth defects in exposed newborns Significant birth defects in 15% of newborn monkeys Birth defects reported in newborn humans Efavirenz should never be used in the first trimester Efavirenz is best avoided entirely during pregnancy 63 Safety of PIs in Pregnancy Studies of blood levels and safety during pregnancy in progress for: Indinavir Ritonavir Saquinavir Nelfinavir Studies in progress for Lopinavir/ritonavir (Kaletra) Amprenavir or fosamprenavir Atazanavir 64 Combination ART and Pregnancy Outcome Development of typical adverse symptoms is common May increase risk of pre-term deliveries Combination therapy started before pregnancy may carry a higher risk of teratogenicity than starting in the 2nd or 3rd trimester Until more information is known, HIV-infected pregnant women who are receiving a successful combination ART regimen should continue (unless on efavirenz or ddI/d4T) 65 Labor and Delivery Care Labor and Delivery Care To facilitate an opportunity for PMTCT: Offer HIV testing for women in labor If a woman accepts an HIV test, provide counseling and rapid test 67 Labor and Delivery Care (2) Critical issues during labor Emotional support Confidentiality Secrecy, disclosure Fear and concern about transmission 68 Labor and Delivery Care (3) Do: Use partogram Perform vaginal cleansing with 0.25% chlorhexidine Follow universal precautions to avoid occupational exposure Limit vaginal examinations during labor Treat acute chorioamnionitis Perform early infant eye and cord care Don’t: Isolate Shave pubic area Perform routine episiotomy Rupture membranes Use vacuum extraction and forceps if not indicated 69 Cesarean Section (CS) Reduces the risk of MTCT Not available and safe in many settings Not routinely performed for women with HIV infection in developing countries Risks of morbidity associated with CS needs to be carefully balanced with risk of MTCT 70 Postnatal Care of Mother Routine postnatal care Infant follow-up Close monitoring for secondary postpartum hemorrhage Early recognition and treatment of infections Continue on HAART if patient is eligible (if on HAART while pregnant) Commence on HAART if patient is eligible (if HAART was not started while pregnant) 71 Postnatal Care of Mother (2) Extra nutrition and micronutrient support Counseling about safe disposal of infectious soiled pads or other garments Family planning counseling Infant feeding counseling Social support 72 Family Planning Discuss family planning BEFORE discharge Assess risk behaviors and counsel on suitable and effective methods Review birth control and infection control Dual protection to prevent and reduce further HIV infection, STIs and pregnancy Data suggests hormonal contraception is less effective with ARVs Access to emergency contraception 73 Infant Follow-up Schedule Follow-up at 6 hours, 6 days, 6 weeks, and every 3 months Do full reassessment, and reclassification for HIV at each visit Virological testing after 6 weeks Cotrimoxazole prophylaxis to all exposed infants 74 Case Studies: PMTCT Case 1 – Introduction A pregnant 22-year-old woman with previously diagnosed HIV infection comes for her first antenatal clinic visit. She is in her first trimester of her first pregnancy. No other complaints. 76 Case 1 Questions 1. What information do you need from her history and physical, in addition to the usual information collected in the antenatal clinic? 2. What laboratory tests will you request? 3. What education and counseling will you provide while you wait for the results of the laboratory tests? 77 Answers: Case 1, Q1 1. What information do you need from her history and physical, in addition to the usual information collected in the antenatal clinic? Why did she have an HIV test initially? Has she disclosed her HIV status to anyone? Has she had any HIV-related illness or treatment? 78 Answers: Case 1, Q1 (2) Do a review of HIV-related symptoms and OIs Perform a full physical exam including assessment for STIs Do gynecological and obstetric evaluation Stage the patient and decide on ART eligibility 79 Answers: Case 1, Q2 2. What laboratory tests will you request? Confirm or repeat HIV test If available, measure CD4+ count and VL RPR and other assessment for STI Other usual antenatal testing Other ARV-related testing if otherwise eligible for combination ARV treatment (CBC, AST, ALT) 80 Answers: Case 1, Q3 3. What education and counseling will you provide while you wait for the results of the laboratory tests? Education and counseling on safe sex practices during pregnancy You, or the counselor in clinic, may discuss with her issues about disclosure of her status to her husband/sexual partner. Ask what kind of support she has 81 Answers: Case 1, Q3 (2) Counsel on risk of MTCT. Explain about use of ARVs to reduce the risk for her newborn. Explain you will do blood tests to see if she needs ART for her own health Educate on adequate nutrition and prenatal care Counseling regarding infant feeding options should begin during antenatal care 82 Case 2 – Introduction A 29-year-old woman in her third pregnancy, delivered a healthy 3.5 kg baby girl an hour after she arrived at the maternity. After the birth, she told the staff she had a positive HIV test done in clinic, but did not take the tablet given her before rushing to the maternity because she did not want her family to know about her HIV infection 83 Case 2 Questions 1. What treatment does she require now? 2. What treatment does her baby require? 84 Answers: Case 2, Q1 1. What treatment does she require now? Treating Sara so as to reduce the risk of intrapartum HIV transmission is no longer an option Sara will need a follow-up visit to assess her immunologic status and to determine if she needs HAART for her own health Needs counseling on disclosure issues Needs counseling on family planning 85 Answers: Case 2, Q2 2. What treatment does her baby require? The infant has not had any nevirapine exposure, as Rosa did not take nevirapine at least 2 hours prior to delivery The infant requires nevirapine 2 mg/kg: First dose within 6 hours post-partum Second dose 48-72 hours post-partum OR NVP one dose plus AZT syrup for 6 weeks 86 Case 3 – Introduction A 21 year-old woman presents to the clinic with pain in her mouth and chest upon swallowing. She has had night sweats and diarrhea for one month. Her usual weight was 58 kg On exam she weighed 51 kg, had no palpable lymph nodes, and had oral candidiasis. She was diagnosed with presumed esophageal candidiasis and treated with oral fluconazole for 3 weeks. Her pain subsided and she began to eat 87 Case 3 – Introduction (2) Based on the esophageal candidiasis, she had WHO Stage IV disease, although no CD4 count was available. She began daily cotrimoxazole for opportunistic infection prophylaxis. She was started on first line HAART with stavudine 30 mg bid, lamivudine 150 mg bid, and nevirapine with the usual dose escalation over 2 weeks. She has been adherent with her medications. The night sweats and diarrhea have stopped, her appetite has increased, and she gained 6 kg 88 Case 3 – Introduction (3) At her 6-month follow-up visit she reports that her menstrual period is 2 months late. A pregnancy test is positive 89 Case 3 Questions 1. 2. 3. 4. Should she continue her antiretroviral therapy? How will you manage her intrapartum care? How will you treat her after her delivery? How will you treat her newborn? 90 Answers: Case 3, Q1 1. Should she continue her ART? She is doing well on a standard ARV regimen, which is safe in pregnancy Does not include efavirenz or ddI+d4T She is still in her first trimester of pregnancy, so risks to her fetus are uncertain Options: Discontinue ARV until 10-12 weeks Continue current ART 91 Answers: Case 3, Q2 2. How will you manage her intrapartum care? Practice safe obstetric procedures ART Option 1: (most practical) Continue stavudine, lamivudine, nevirapine as usual ART Option 2: Give zidovudine, lamivudine, nevirapine at standard doses 92 Answers: Case 3, Q2 (2) ART Option 3 Zidovudine 600 mg loading dose by mouth followed by 300 mg by mouth every 3 hours till delivery Lamivudine 150 mg by mouth every 12 hours Nevirapine 200 mg twelve hours daily as she used to take it 93 Answers: Case 3, Q3 3. How will you treat her after her delivery? She can resume her usual antiretroviral combination after delivery She should be counseled on infant feeding There is no information so far on the effects of maternal ART on risks of HIV transmission through breast milk 94 Answers: Case 3, Q4 4. How will you treat her newborn? Nevirapine syrup 2 mg/kg at 48-72 hours of life as usual for HIV-exposed infants plus AZT syrup for 4- 6 weeks Infant starts cotrimoxazole at 6 weeks Explain testing of infant at 18 months 95 Key Points Women are more vulnerable to HIV due to biological, economic, social, and cultural factors Women with HIV have special gynecological needs and concerns Women and men with HIV progress at similar rates; ART guidelines are not gender specific 96 Key Points (2) All pregnant women should know their HIV status in order to protect their children and themselves Women with AIDS are more likely to suffer from pregnancy-related complications Pregnant women who present with CD4 <200/mm3 irrespective of WHO stage should be started on first line treatment: AZT, 3TC, NVP 97 Key Points (3) Pregnant women should not receive efavirenz or ddI/d4T Effective strategies are available for reducing the risk of MTCT Nevirapine can reduce the risk of MTCT by 41% Use of HAART can reduce MTCT to less than 2% 98