Global Summary of the HIV/AIDS Epidemic, December 2001

1. Reproductive Health in HIV Infected WomenHelene Bernstein, M.D.,Ph.D.Assistant ProfessorDepartment of Obstetrics and GynecologyDavid Geffen School of Medicine at UCLA

2. Global Summary of the HIV/AIDS Epidemic,December 2001 Number of people living with HIV/AIDS Total 40 millionAdults 37.2 million Women 17.6 million Children 2.7 million About 14,000 new HIV infections a day in 2001 12,000 are in persons aged 15 to 49 years, of whom: -almost 50% are women -about 50% are 15–24 year olds

3. Care of the HIV Infected Woman • Primary Care • Gynecological Care • Obstetric Care

4. “HIV History” • Year of diagnosis • How HIV was acquired • HIV status of current partner • Prior treatment history, including viral load and CD 4+ T cell counts on and off therapy • History of gynecologic problems and HIV-affected pregnancies • Supportive care needs

5. Preconceptual Counseling • Educate patients about perinatal transmission rates • To avoid unintended pregnancies • Counsel patients about safe methods to conceive • Choose anti-retrovirals which are known to be effective in reducing perinatal HIV transmission • Attain a stable, maximally suppressed viral load • Optimize medical and nutritional status

6. Vaccination • Kiiled virus, toxoid, or recombinant vaccines are safe in pregnancy • Routine vaccinations • Hepatitis B • Pneumonia vaccine • Influenza vaccine Rubella vaccine and other live, attenuated vacicnes may be given post-partum

7. Gynecologic Issues in HIV Infected Women • Abnormal uterine bleeding • Pap smears • Infections/STD screening: GC, chlamydia, HSV, genital ulcerative disease • Contraception • Breast Examinations-mammograms at appropriate age

8. Abnormal PAP smear:HPV Virology and Epidemiology • part of a heterogeneous group of double-stranded DNA viruses • There are over 100 subtypes of HPV, categorized depending on their association with neoplasia and cancer. • Common low risk subtypes of HPV are 6 and 11 (other subtypes: 42, 43, 44), which are found in condylomas. • HPV subtypes found in cervical cancer specimens are 16 and 18 (other high risk subtypes: 31, 33, 35, 39, 45, 50, 51, 53, 55, 56, 58, 59, 64, and 68). • HPV DNA is found in over 99% of cervical cancer specimens. • HPV infects epithelial cells, high risk HPV genotypes integrate into the host genome and express viral oncogenes E6 and E7 which can lead to dysplasia.

9. HPV: Virology and Epidemiology • Over 50% of sexually active adults have been infected with at least one subtype of HPV, but most infections are transient • Risk factors for developing dysplasia/cancer include: more than six sexual partners, cigarette smoking, early age of first coitus, history of STDs and immunosuppression • HIV-infected women have been found to have a higher prevalence of HPV, higher likelihood of multiple subtypes, and greater prevalence of oncogenic subtypes than in HIV-uninfected women • In HIV-infected women the frequency of HPV infection increases with decreasing CD4 counts and/or higher viral loads.

10. Manifestations of HPV disease in women 1. Abnormal PAP smear • 30-60% of PAP smears in HIV-infected women are abnormal • 15-40% dysplasia • 10-11 times higher rate than HIV negative women • Dysplasia is more likely to involve other areas of the lower genital tract in HIV-infected women (vagina, vulva, perianal area) • There maybe an increased rate of progression of dysplasia in HIV-infected women 2. Invasive cervical cancer- an AIDS defining illness • There is an increased rate of cervical cancer in HIV-infected women, particularly those aged 20 to 34, African American and Hispanic women • Disease is characterized by advanced stage at presentation, metastasis to unusual locations, poor response to therapy, higher recurrence level, shorter interval to death. 3. Other lower genital tract neoplasia

11. HPV Screening • PAP smears • sensitivity and specificity is comparable to HIV-negative women • Would initially do every six months, then annually after two normal PAPs, unless CD4 count is below 200. • ThinPrep-liquid based media increases sensitivity and decreases inadequate smears, can also perform HPV testing using this specimen, use if possible. • HPV testing-make sure it will tell you subtypes! • Colposcopy-not recommended for screening

12. PAP Smear: Cytologic Reporting • Specimen adequacy: drying, inflammation • Interpretation: • Negative for intraepithelial lesion or malignancy • Atypical squamous cells-of undetermined significance (ASC-US) -cannot exclude HSIL (ASC-H) • Atypical glandular cells-NEEDS FURTHER WORKUP • Low-grade squamous intraepithelial lesions (LSIL) corresponds to CIN 1 • High-grade squamous intraepithelial lesions (HSIL) combines CIN 2, 3 and carcinoma in situ

13. Management of PAP Smears • If abnormal PAP (anything not negative): • Colposcopy with biopsy, look at entire lower genital tract • If ASC or LSIL • PAPs q4-6 months • If HSIL/CIN 2-3 • Refer to gynecologist • Loop electrosurgical excision procedure (LEEP), conization, ablation (only if biopsied lesion on ectocervix) • Post treatment: PAPs q3-4 months for 1 year then twice yearly • Consider vaginal 5-fluorouracil cream to decrease recurrence • HAART-regression, decrease incidence of dysplasia?? • If Cancer- Refer to gynecologic oncologist

14. Conclusions • Cervical dysplasia in the HIV-infected woman is detectable and treatable -cervical cancer can be deadly. • Cervical cancer can be largely prevented by regular screening and treatment for dysplasia • HIV-infected patients should be evaluated for dysplasia in other regions of the lower genital tract

15. References Stier, E. Cervical neoplasia and the HIV-infected patient. Hematol Oncol Clin N Am. 2003. 17:873-87 Abularach, S. and Anderson, J. Gynecologic problems. In A guide to the clinical care of women with HIV.2001. pg 149-96. Available at http://hab.hrsa.gov/publications/womencare.htm

16. Management of HIV in Pregnancy

17. Treatment With Antiretrovirals Decreases the Vertical Transmission Rate of HIV • Without treatment 15-40% of babies get HIV • AZT reduces vertical HIV transmission by 2/3 (to 8%) • In the US most women are treated with HAART, leading to a HIV transmission rate of 1%

18. HIV-Infected Pregnant Women Have Better Outcomes than Pregnant Women With: • Diabetes • High Blood Pressure • Autoimmune Diseases: Lupus

19. HIV in Pregnancy: Goals Appropriate care for the mother -therapy for maternal indications -opportunistic infection prophylaxis and treatment 2. Limit the risk of perinatal HIV transmission

20. ART Therapy in Pregnancy • If patient has a viral load>1000 and is willing and able to be compliant: • Start HAART, a typical pregnancy regimen is: • AZT • 3TC • Nelfinavir • If viral load < 1000 discuss HAART versus AZT monotherapy with patient • When to start?

21. Special Considerations on ART by HIV+ Pregnant Women and Their Infants • Issues of special concern: • Drugs with higher teratogenic risk (efavirenz, hydroxyurea). • Combination antiretroviral therapy and preterm delivery? • Protease inhibitors and hyperglycemia. • Mitochondrial toxicity and nucleoside analogues: • Pregnancy – lactic acidosis, hepatic steatosis, pancreatitis (d4T/ddI fatalities). • Fetus/infant – theoretical mitochondrial toxicity with in utero exposure.

22. Maternal Factors Which Influence Mother to Child Transmission of HIV • Viral load • Low CD4 Count • Advanced HIV disease • Pregnancy complications: preterm birth, Chorioamnionitis, placental abruption/hemorrhage • Sexually transmitted diseases during pregnancy • Illicit Drug Use • Breastfeeding • Treatment of Maternal disease

23. Perinatally Acquired AIDS Cases* by Quarter-Year of Diagnosis, 1985-1999, United States 300 250 200 150 Number of Cases 100 50 0 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 Quarter-Year of Diagnosis *Adjusted for reporting delays and unreported risk; data reported through June 2000

24. Prenatal Testing • Ultrasound • Triple screen • Antenatal karyotype determination if indicated • Patient must be counseled about the risk of HIV transmission during procedure • Data is limited

25. Special Considerations for Prenatal Care • More frequent visits,q1-4 weeks when starting therapy • Multidisciplinary approach, involve social work, case managers, peer counselors, pediatricians • Check viral loads and CD4 counts monthly when starting or changing therapy and in each trimester after viral load becomes undetectable • Screen for hepatitis B and C, and consider evaluating for toxoplasmosis, CMV exposure • Vaccinate patients as appropriate • Emphasize adherence to antiretroviral therapy

26. Disclosure • To partner • To family • Although the decision to disclose her HIV status is that of the mother, given that the infant will be discharged on prophylactic medications, we encourage disclosure not only to sexual contacts, but to close family members who may share in the care of the infant

27. Does an elective cesarean section protect against HIV transmission? • Patients on no antiretroviral therapy • Patients on AZT monotherapy • Patients with a measurable viral load above 1000 • But, to be protective the elective c-section must be done prior to labor or SROM

28. Intrapartum Management • Goal is to minimize interval to delivery, ie aggressively augment labor as appropriate • Do not rupture membranes • Avoid invasive monitoring • Avoid episiotomy or instrumental delivery when possible

29. Post-Partum Treatment for the Infant • AZT Prophylaxis for 6 weeks, medications may be expanded dependent on maternal status • Bactrim for 6 months, PCP prophylaxis • Child is considered uninfected after 3 negative viral loads

30. Studies of Potential ZDV Carcinogenicity • ZDV carcinogenic in vitro (all nucleosides are) • Benign vaginal tumors in mice- probable topical effect • Two transplacental studies in mice • NCI: high dose, third trimester only, increased tumors in adults • GW: lower dose pregnancy and pups, no increase in tumors • Human data : No tumors in > 1,000 person-years • Surveillance ongoing

31. Antiretroviral Pregnancy Registry (Prospective Cases only through 1/31/02) • • 2416 prospectively reported cases with ARV • exposure anytime during pregnancy. • • Birth defect rates after first trimester exposure • ZDV 17/684 (2.5%) – Nelfinavir 8/256 (3.1%) • 3TC 18/687 (2.6%) – Stavudine 5/250 (2.0%) • Other agents, too few exposures to report rates. • • No pattern of defects in prospective or • retrospective reports.