Women and HIV: Emerging Issues in Clinical Management Karen P. Beckerman, MD Assistant Professor Obstetrics, Gynecology and Reproductive Sciences University of California, San Francisco 30 November 2001

Epidemiology in the U.S. Heterosexual transmission of HIV-1 Manifestations of HIV in women Initiating therapy in women Reproductive Health and HIV Preconceptional and early pregnancy counseling Vertical Transmission Principles of care during pregnancy The global epidemic

U.S. Total Cases: as of June 1999 Total711,344 Men588,124 Women114,621 Heterosexual 40 % Unknown 39% IV Drug Use 29% Transfusion <1% Children 8,590

Epidemiology In the United States, women represent the fastest growing group of new infections: %19%20%23%

Heterosexual Transmission among U.S. Youth, 1999 AgeWomenMen % 7% % 7% Overall, 54% of youth did not report a risk factor.

Heterosexual Transmission in the rural U.S. West:52% Southeast:58% 33% of new infections occur among women 2/3 of men and women are infected sexually 69% of women had young children at home

Heterosexual Transmission, Observations: These estimates are low. “IVDU” is listed where any history exists. Most unknowns are probably heterosexual.

A new female patient in your office is likely to be: From any socioeconomic class. The mother of small children (who must be tested). A prostitute An IV drug user And unlikely to be:

Manifestations of HIV disease among women Male  female transmission is 2-10x more efficient than female  male More virus is found in semen than in vaginal fluids Vaginal surface area >> male urethra and foreskin

Manifestations of HIV disease among women Women may be more likely than men to be diagnosed by screening alone. Most common presenting complaint in women is candidal esophagitis. Nevirapine rash is more common in women. Women without transmission risk factors often go undiagnosed when presenting with recurrent pneumonia, candidiasis or cervical dysplasia.

Manifestations of HIV disease among women: Seborrheic dermatitis WomenMen axilla face between breasts chin groin nasal area external ear auditory canal axilla

Manifestations of HIV disease among women Viral load was 50% lower in women than men More rapid declines in CD4 over time Findings may be confounded by race Anastos et al., 2000, JAIDS.24:218

Manifestations of HIV disease among women Other than reproduction, there are not major gender differences in the natural history of HIV disease.

Initiating antiretroviral Therapy (NIH Guidelines 13 August 2001: hivatis.org) When symptomatic: any CD4 and any viral load Asymptomatic with AIDS, CD4<200  treat. Asymptomatic with CD4 between 200 & 350  offer treatment. Asymptomatic with CD4 > 350, VL>55,000 *3 year risk of AIDS >30%  recommend treatment, or  defer with frequent monitoring Asymptomatic with CD4 > 350, VL <55,000  many experts would defer therapy

Initiating antiretroviral Therapy (NIH Guidelines 13 August 2001: hivatis.org) For women with CD4 > 350, clinicians may consider beginning therapy at lower VL than in men. However, we have insufficient data to recommend a VL cut-off for women.

Reproductive Health among HIV-infected Women Baseline colposcopy at HIV diagnosis Pelvic and cervical pap smear every six months, at least initially The role of anal Pap smears remains to be defined Treat genital warts Test for other sexually transmitted diseases

Reproductive Health among HIV-infected Women: CERVICAL DYSPLASIA & HPV Immunosuppression is associated with increased susceptibility to HPV Cervical dysplasia is 2x as common among women with AIDS diagnosis Standard cervical pap tests may miss vaginal, vulvar or anal dysplasia Colposcopy for ASCIS, AGCUS, low grade and high grade SIL or persistant inflammation

Contraceptive and Safe Sex Counseling Must be addressed! Barrier method (male or female condom) is required for STD protection. Impact of hormonal contraception on HIV shedding? Bioavailability of ethinyl estradiol in contraceptives may be significantly reduced by ritonavir, nelfinavir or nevirapine.

Contraceptive and Safe Sex Counseling HIV-infected women must have access to all approved forms of contraception! Back-up methods (tubal ligation, hormonal contraception) to barrier methods are acceptable and recommended.

Preconceptional and Early Pregnancy Counseling Availability of antibody testing NON-DIRECTIVE and SUPPORTIVE for client’s reproductive choice: -Pregnancy does not affect course of HIV in the industrialized world -It is quite possible to have a normal pregnancy and an uninfected baby -For all women, early abortion is generally safer than pregnancy

First things first: Safe shelter Food Self-determination

Preconceptional and Early Pregnancy Counseling Confirm serostatus, especially in areas of low sero-prevalence where the positive predictive value of a single test may be low Obstetrical and gynecological history History of HIV care, antiretrovirals, resistance Physical examination

Preconceptional and Early Pregnancy Counseling: LABORATORY STUDIES: Rubella and varicella antibodies Toxoplasma antibody CMV serostatus Hepatitis serology Syphillis serology Chlamydia, GC testing Baseline chest radiograph

Preconceptional and Early Pregnancy Counseling: Optimization of care: If already taking ART, optimize -Switch from efavirenz to nevirapine -Consider switch from amprenavir to Kaletra (ritonavir/lopinavir) -Adherence, current and future Discuss and optimize OI prophylaxis Address nutritional needs Consider extra folate supplement Optimize control of other medical conditions

Preconceptional and Early Pregnancy Counseling: Therapeutic options during pregnancy No medications Prophylaxis alone Other effects of ART (anemia, resistance, etc.) Options for labor and delivery Prophylaxis for neonates Diagnostic procedures for exposed infants

Pneumocystis Pneumonia during the first year of life carries a >90% fatality rate

Diagnostic procedures for exposed infants: Aimed at diagnosis at earliest time to intervene prior to clinical immunodeficiency. Viral test (DNA-PCR or RNA-PCR) at: birththree months one monthsix months Antibody test at: 12 months, 18 months or until antibody clears Viral test at three months is highly predictive of infection status *Seroreversion is gold standard*

Prophylaxis procedures for exposed infants: Zidovudine syrup 2mg/kg q 6h for six weeks Trimethoprim-sulfa OI prophylaxis from 6 weeks to 6 months Recommendations do not exist for dealing with maternal zidovudine resistance Rarely, an infant might be given more than one medication for prophylaxis Some authorities are allowing mothers not to give TMP-sulfa when risk of transmission is low

Preconceptional and Early Pregnancy Counseling: Review adherence issues during pregnancy and post-partum Discuss guardianship and other legal issues Domestic violence issues Discuss fertility, conception and safe sex Risks of vertical transmission and pediatric HIV disease Discuss advanced maternal age Neural tube defect screening

Preconceptional and Early Pregnancy Counseling: Access to clinical trials and other research Peer counseling and peer support

Preconceptional and Early Pregnancy Counseling Observations: Isolation is a major problem for infected women everywhere. Many have never met another HIV- infected woman. Most have never even heard of an infected mother or pregnant woman. One-half of US HIV-infected women report domestic violence.

Preconceptional and Early Pregnancy Counseling Risk of vertical transmission: Among women taking potent antiretroviral cocktails risk is not published - may be close to 1%. Exposed infants will need six or more blood tests before two years of age to rule out HIV infection.

Vertical Transmission Mechanisms: Unknown! Exposure to maternal secretions? Exposure to maternal blood at delivery? Via the placenta?

Vertical Transmission Maternal risk factors: Maternal immune status: maternal CD4 Disease activity: maternal viral load ( Garcia et al., NEJM 341:394) Antiretroviral prophylaxis Antiretroviral therapy Prior infected child Weight loss, Tb, OIs

Length of ruptured membranes(hours) 

Vertical Transmission Obstetrical risk factors: Length of ruptured membranes Prematurity, low birth weight Immune activation during pregnancy or at delivery? Evidence of chorioamnionitis: infection or inflammation of membranes/placenta

Principles of care of the HIV-1 infected pregnant mother First things first: Safe housing Adequate nutrition Transportation Self-determination for: reproductive choice treatment & prophylaxis

Priniciples of care of the HIV-1 infected pregnant mother When mother is already on stable HAART with good control: Encourage continuation of regimen through 1st trimester. >20,000 reports to the Antiretroviral Pregnancy Registry - no increase in congenital malformations. Offer option of brief treatment interruption. Advise patient that VL will certainly rebound, but that stopping all ART at once may be safe for a few months

Priniciples of care of the HIV-1 infected pregnant mother When mother is not on stable HAART, or is experiencing virologic breakthrough: Do not start therapy or change therapy until the second trimester. >Nausea and vomiting during the first trimester make it a very poor time to start new therapies. Offer: >Continuation of therapy with a change in 2nd trimester. >Brief treatment interruption. >Start of therapy in 2nd trimester.

Priniciples of care of the HIV-1 infected pregnant mother Antiretrovirals that should be avoided if possible: EFAVIRENZ: Unpublished primate data show high incidence of neural tube defects. No reports in humans. No indication, per se, to abort pregnancy. Multiple ultrasound and blood tests can rule out neural tube defects. Consider a switch to nevirapine.

Priniciples of care of the HIV-1 infected pregnant mother Antiretrovirals that should be avoided if possible: AMPRENAVIR: Unpublished reports of abnormal calcification of bones. Human data are lacking. Consider a switch to another highly potent agent or combination, such as lopinavir/ritonavir.

Priniciples of care of the HIV-1 infected pregnant mother Antiretrovirals that should be avoided if possible: STAVUDINE/DIDANOSINE (D4T/ddI): High potency nRTI combination. Particularly effective in the setting of pan-resistance and virologic breakthrough. Given alone short term in South Africa, was highly effective at preventing MCT, without lactic acidosis. Reports of lactic acidosis during pregnancy. If needed, requires very frequent monitoring of liver transaminases.

Prophylaxis for Opportunistic Infection Trimethoprim-sulfa Dapsone Azithromycin >may all be used safely during pregnancy >pregnancy is not a good time to stop OI prophylaxis

Principles of care of the HIV-1 infected pregnant mother Protection of mothers from mono- and dual therapies likely to induce ART resistance:

Low Fidelity HIV-1 Replication

Two polymerases without proofreading activity HIV-1 reverse transcriptase Cellular RNA polymerase Two RNA copies per virion Insertions and deletions are common RNA strand breaks force template switching Uracil incorporation into proviral DNA Especially in resting cells Low Fidelity HIV-1 Replication

Pregnancy and ART resistance in Uganda NVP single dose prophylaxis: HIVNET 006 & 012 Single dose to mother + single dose to infant Transmission fell from 25 to 13%  10 of 46 mothers studied 6 weeks to 6 months later had detectable resistance  Of the 36 infected infants, 8 had detectable nnRTI resistance at 6 weeks of age.

Pregnancy and ART resistance in the developed world

Principles of care of the HIV-1 infected pregnant mother Protection of mothers from mono- and dual- therapies likely to induce resistance: Nevirapine prophylaxis (even one dose) is highly likely to result in nnRTI resistance if not given in a safe combination. In the U.S., nevirapine prophylaxis given in addition to standard ART resulted in no benefit to mother or baby, but did cause significant induction of nnRTI resistance. (Dorenbaum, PACTG 316, CROI, 2001)

Pregnancy and ART resistance in the developed world Zidovudine/lamivudine (AZT/3TC) induces resistance (M184V) at same frequencies in pregnant women as in men In one study, 4 of 5 mothers developed M184V (Clark, J Med Virol.59:364) M184V can be transmitted to neonates

Pregnancy and ART resistance in the U.S. and Japan Are these data relevant to us today? Unfortunately, YES. ACTG 185: late 1990s  86% received ZDV 14% received ZDV/3TC  30% of mothers had nRTI resistance by delivery  These mothers were 3 times more likely to transmit virus to their infant (p=0.03)

Principles of care of the HIV-1 infected pregnant mother Protection of mothers from mono- and dual- therapies likely to induce resistance: Women refusing 3 medications should be offered zidovudine prophylaxis, never Combivir alone. Combivir Alone

Priniciples of care of the HIV-1 infected pregnant mother Aggressive use of combination antiretroviral therapy to achieve durable suppression of maternal HIV replication and to protect mother from induction of antiretroviral resistance: Offer 3 or more medications Twice daily dosing

Principles of care of the HIV-1 infected pregnant mother Cytochrome p4503A reductase activity: AUC 8 for indinavir is markedly suppressed late in pregnancy p450 3A activity is significantly increased in the third trimester (Homma et al., 2001; Hayashi et al. 2001) Increased p450 3A activity in late pregnancy is reversed by ritonavir, allowing twice daily dosing, for example, RTV200mg/IDV800mg q 12 h

Principles of care of the HIV-1 infected pregnant mother Aggressive use of combination antiretroviral therapy to achieve durable suppression of maternal HIV replication and to protect mother from induction of antiretroviral resistance: When likelihood of non- adherence is high, do not offer nevirapine If mother does not need therapy for her own health, HAART can be safely stopped post-partum

Route of delivery Informed maternal choice: Retrospective evidence of prevention of vertical transmission by elective cesarean delivery Hours of membrane rupture 

Route of delivery Informed maternal choice: No data exist that demonstrate a benefit of elective cesarean to mother or baby when mother is receiving potent combination therapy.

University of California/San Francisco General Hospital

San Francisco,

Length of rupture of membranes, (hours) Shaffer et al., Viral Load and Transmission

Control of maternal viral load appears to be highly protective even in the setting of prolonged rupture of membranes

November 2001: u> 40 million infected u>8,000 deaths per day u600 new infections per hour ua child dies every minute

By 2010, >42 million orphans. They will suffer greatly, whether they are infected...

…or not.

Japanese AIDS Research Society Dr. Aikichi Iwamoto Dr. Atsushi Ajisawa Dr. Makoto Aoki Ms.Narumi Hori GlaxoSmithKline Medicus Tokyo