Artist: Kathryn Love STIs in Women Heidi M. Bauer, MD MPH California Dept of Public Health STD Control California STD/HIV Prevention Training Center UCSF Primary Care Medicine October 3, 28 *Top 1* STI Highlights 1. Socio-cultural context and women s STI risk 9. Low rates of chlamydia screening 8. Fewer antibiotics for gonorrhea 7. Expedited partner treatment 6. CT/GC re-testing at 3 months 5. New trich treatment option 4. Herpes serology testing 3. Herpes suppressive treatment 2. HPV testing 1. HPV vaccine Karen 19 y.o. African American woman from Alabama recently moved to SF to start school Presents with vaginal discharge, itching and bumps Sexual debut 1 year prior, one lifetime sex partner male, age 27 no longer together Didn t use condoms because I thought I was in love LMP 1 days prior External genitalia STD Atlas, 1997 1
HIV (-) Syphilis (-) Chlamydia (+) Gonorrhea (+) STI Test Results What does this case illustrate? 19 y.o. African American woman from Alabama recently moved to SF to start school presents with vaginal discharge, itching and bumps Sexual debut 1 year prior, reports one lifetime sex partner male age 27 no longer together Didn t use condoms because she thought I was in love Why are Young Women at Higher Risk for STIs? Female anatomy Large mucosal surface area Prolonged exposure to secretions Young age Cervical ectopy Immunologically naïve Thinner cervical mucus Infections asymptomatic Delay in seeking care Increase risk of complications 2
Cervical Ectopy STD Atlas, 1997 Why are Young Women at Higher Risk for STIs? Social influences Power differentials relationships Differential behavioral norms for partners Limited female-controlled barrier methods Shame and stigma Access to sexuality information Healthcare access Greater screening opportunities Financial barriers Challenges to partner treatment World War II public health poster National Library of Medicine World War II public health poster National Library of Medicine 3
Overview of Complications of STIs in Women Infertility Ectopic Pregnancy Chronic Pelvic Pain Upper Tract Infection STIs Systemic Infection Chronic Disease HIV Infection Cancer Pregnancy Complications & Neonatal Infections STI Screening for Women Sexually Active adolescents & up to age 25 Routine chlamydia and gonorrhea screening Pap 3 years after sexual debut Others STDs and HIV based on risk Women over 25 years of age STD/HIV testing based on risk factors Pregnant women (first trimester) HIV, Syphilis serology, Hep B sag, Chlamydia Gonorrhea (<25 years of age) Hep C based on risk Consider BV if high risk pregnancy Pap as indicated Chlamydia & Gonorrhea 4
CT & GC Highlights Chlamydia and Gonorrhea Rates: Total and by sex: United States, 1987 26 CT screening unacceptably low despite non-invasive tests Antibiotic resistant GC Expedited partner treatment (EPT) Re-testing after treatment Rate (per 1, population) 6 Men Women 48 Total 36 24 12 1987 89 91 93 95 97 99 21 3 5 Rate (per 1, population) 4 Male Female 32 Total 21 Target 24 Chlamydia Gonorrhea 16 8 1987 89 91 93 95 97 99 21 3 5 Chlamydia and Gonorrhea Age- and sex-specific rates: United States, 26 Men Rate (per 1, population) Women 3 6 Age 6 24 3 24 18 12 12 18 Chlamydia and Gonorrhea Rates by race/ethnicity and sex: United States, 26 Men Rate (per 1, population) Women 2 4 Race 4 16 2 16 12 8 8 12 11.6 1-14 121.5 317.3 AI/AN 1262.3 545.1 15-19 2862.7 856.9 2-24 2797. 48.8 25-29 1141.2 222.2 3-34 415.7 12.8 35-39 174.2 Chlamydia 59.2 Asian/PI 21.2 741.2 Black 176.9 Chlamydia 65.1 4-44 69. 27.8 45-54 25.6 211. Hispanic 761.3 9.1 55-64 6.8 2.8 65+ 2.2 66. White 237. 173.4 Total 517. 173.1 Total 516.4 Men Rate (per 1, population) Women 75 15 Age 15 6 75 6 45 3 3 45 6.3 1-14 35.1 Gonorrhea 75 6 45 3 15 Race 15 3 45 6 75 99.9 AI/AN 175.6 Gonorrhea 279.1 15-19 647.9 454.1 2-24 65.7 19.6 Asian/PI 22.6 32.9 25-29 294.9 185.7 3-34 125.5 72.7 Black 618.1 13.8 35-39 65.7 93.5 4-44 33.9 53. 45-54 12.9 7.1 Hispanic 85.3 18.4 55-64 2.9 4.2 65+.7 28.3 White 44.4 117.1 Total 124.6 117.1 Total 124.6 5
Who Needs Chlamydia Screening? ALL sexually active adolescent and young women <26 years Pregnant women MSM Others according to risk: new/multiple partners, partner with other partners, history of CT, other STDs, high prevalence settings Chlamydia Prevalence Monitoring, Percent Positive for Females Ages 15 19 and 2 24 by Health Care Setting, California, 26 Percent Positive. 3 25 2 15 1 5 6.1 4.1 Managed Care Organization 15 19 2 24 8 5.3 Family Planning Clinics 6.3 5.9 4.3 3.6 * These two venues target adolescents primarily. 4.4 College Sites Teen Clinics School-Based Sites* 13.1 Juvenile Detention* 25.1 15.4 STD Clinics Source: California Department of Public Health, STD Control Branch; Los Angeles Infertility Prevention Project; and San Francisco Infertility Prevention Project CA DPH STD Control Branch (rev 7/27) Chlamydia Positivity among 15- to 24-year-old women tested in family planning clinics by state: United States and outlying areas, 26 5. 11.3 6.4 6.7 5.8 4.6 6.5 6.4 7.3 6. 8.6 6.3 9.7 8.2 6.9 5.9 6.1 1.3 7.2 Positivity (%) <5. 5.-9.9 >=1. Puerto Rico 6.4 Virgin Is. 16.9 Note: Includes states and outlying areas that reported chlamydia positivity data on at least 5 women aged 15-24 years screened during 26. 6.7 6.2 7.1 6.2 8.1 7.9 7.1 7.9 SOURCE: Regional Infertility Prevention Projects; Office of Population Affairs; Local and State STD Control Programs; Centers for Disease Control and Prevention 7.6 14. 6.5 14.5 5.6 7.8 1.3 2.8 11.5 5.5 4.9 7.8 7.8 4.6 4.4 VT 3.9 NH 4.1 MA 4.7 RI 6.7 CT 5.7 NJ 7.5 DE 7.7 MD 5.7 DC 7.2 (n= 8) (n= 38) (n= 7) Estimated Chlamydia Screening Coverage (HEDIS), Females 16 26, USA and California, 1999 25 Percent Screened. 1 9 8 7 6 5 4 3 2 1 1999 2 21 22 23 24 25 Natl MCO Natl Medicaid MediCal MC Cal HMO FPACT National California 1 4 Source: National Committee on Quality Assurance; California DHS Division of Medi-Cal Managed Care; Kaiser Permanente Northern CA; California DHS Office of Family Planning CA DPH STD Control Branch (rev 7/26) 6
Nucleic Acid Amplification Tests Highest sensitivity Able to detect up to 4% more infections Less dependent on specimen collection and handling Noninvasive Urine and self-collected vaginal swabs Pelvic exams not necessary Who Needs Gonorrhea Screening? Sexually active women (including pregnant women) under age 25 MSM Others according to risk: previous GC infection, other STD, new/multiple partners, partner with other partners commercial sex, drug use www.std.ca.gov for CA GC screening guidelines What is your primary treatment for uncomplicated gonorrhea? Gonococcal Isolate Surveillance Project (GISP) Percent of Neisseria gonorrhoeae isolates with resistance or intermediate resistance to ciprofloxacin, U.S., 199 26 A. Ceftriaxone IM injection B. Oral cephalosporin (e.g., cefixime or cefpodoxime) C. Ciprofloxacin or other fluoroquinolone D. Azithromycin 2 g E. Other Percent 16. 12. 8. 4.. Resistant Intermediate resistance 199 91 92 93 94 95 96 97 98 99 2 1 2 3 4 5 6 Note: Resistant isolates have ciprofloxacin MICs 1 µg/ml. Isolates with intermediate resistance have ciprofloxacin MICs of.125 -.5 µg/ml. Susceptibility to ciprofloxacin was first measured in GISP in 199. 7
Gonorrhea Treatment Uncomplicated Genital/Rectal Infections AVOID fluoroquinolones Recommended regimens: Ceftriaxone 125 mg intramuscularly in a single dose OR Cefixime 4 mg orally in a single dose * Co-treat for chlamydia unless ruled out What method do you use most often to get sex partners treated? A. I ask the health department to contact partners B. I ask patients to notify their partners C. I ask patients to bring their partners to clinic for testing and treatment D. I give patients medication/prescriptions for their partners E. I don t discuss sex partner treatment (UPDATED April 27) Percent 16 14 12 1 8 6 4 2 Infection During Follow-up Among Patients Completing The EPT Trial Standard care Expedited care 1.6 P=.2 3.4 13.2 P=.17 1.8 Gonorrhea Chlamydia Gonorrhea or N=358 N=1595 Chlamydia Golden NEJM 25 13 P=.4 9.9 N=186 Expedited Partner Treatment Expedited partner treatment for CT and GC safe and effective First line management is clinical evaluation Concern regarding co-morbidities (e.g., PID in women, HIV in MSM) www.std.ca.gov for CA EPT guidelines 8
Legal Status of EPT in the U.S. Reinfection of Women with Chlamydia Within 12 Months of Initial Infection 4 Reinfection (%) 3 2 1 2 4 6 8 1 12 Months Follow-up www.cdc.gov/std/ept as of 28 Hosenfeld, unpublished review of 17 active cohort studies Our New Motto for CT/GC: Screen Treat Treat Screen Trichomoniasis Highlights New point-of-care tests New treatment regimen: Tinidazole 9
POC Tests for Trichomonas Trichomoniasis Treatment Detects Type of test Manufacturer Time to results Sensitivity Specificity DNA hybridization, colorimetric test Becton Dickinson 45 min Affirm TM VP III T. vaginalis, G. vaginalis, and C. albicans Gardnerella: 84% Trich: 92% Candida: 78% 96-98% OSOM Trichomonas Rapid Test T. vaginalis Color immunochromatographic capillary flow test; dipstick Genzyme 1 min Vaginal swab: 83% Saline wet mount: 75% >97% Recommended regimen: Metronidazole 2 g PO x 1 ADDED: Tinidazole 2 g po x 1 Alternative regimen: Metronidazole 5 mg PO BID x 7d Recommended regimen in pregnancy: Metronidazole 2 g PO x 1 * Metronidazole category B and Tinidazole is category C in pregnancy Genital Herpes Highlights Genital Herpes Uses for type-specific serologic tests When to use suppression therapy to prevent transmission 1
Percent 4 32 24 16 8 Genital herpes simplex virus type 2 - Seroprevalence according to age in NHANES* II (1976-198) and NHANES III (1988-1994) Age Group NHANES II NHANES III 12-19 2-29 3-39 4-49 5-59 6-69 7+ Note: Bars indicate 95% confidence intervals. *National Health and Nutrition Examination Survey Rationale for HSV-2 Serologic Screening Up to 8% of people with HSV-2 unaware of their infection Patients can be taught to recognize symptoms; treat as needed Awareness may reduce risky behavior, increase disclosure, and protect partners Suppression therapy reduces HSV-2 transmission CA Guidelines at www.std.ca.gov Type-Specific HSV Serology Tests HSV-1 and HSV-2 Immunoblot IgG (Focus Technologies) Sensitivity 97-1%, Specificity 96-97% HSV-1 and HSV-2 ELISA IgG (Focus Technologies) Sensitivity 96-1%, Specificity 94-98% Captia ELISA HSV-2 (Trinity Biotech) Sensitivity 9-92%, Specificity 91-98% Biokit HSV-2 & Sureview HSV-2 (Biokit & Fisher Scientific) Point of care tests Sensitivity 93-96%, Specificity 95-98% Who Should Be Tested for HSV-2 Antibodies? Type-specific HSV serologic assays might be useful for: Recurrent genital symptoms or atypical symptoms with negative HSV cultures Clinical diagnosis of genital herpes without lab confirmation A partner with genital herpes Some specialists believe HSV serologic testing should be included in a comprehensive STD evaluation among: Persons with multiple sex partners HIV infection MSM at increased risk for HIV acquisition 11
How do you prescribe HSV-2 suppressive treatment? A. Only sporadically for special purposes (e.g., wedding, vacation, midterms) B. Only with demonstrated frequent severe outbreaks C. Anyone who wants to reduce transmission to partners D. Pregnant women prior to term E. All of the above Genital Herpes Prevention of Sexual Transmission Suppressive therapy is safe and effective Suppression should be encouraged among discordant heterosexual couples Suppressive therapy probably reduces transmission when used by persons who have multiple partners (including MSM) and by those who are HSV-2 seropositive without a history of genital herpes Counsel regarding condoms, disclosure, abstinence during recurrences Rates of Transmission of HSV-2 to Susceptible Partners is Reduced with Once-Daily Suppressive Therapy 1484 heterosexual couples randomly assigned to take 5 mg of valacyclovir or placebo once daily for 8 months Serum samples collected monthly from susceptible partners for HSV analysis The valacyclovir group showed decreased transmission lower frequency of shedding fewer copies of HSV-2 DNA when shedding occurred Percent Transmission 4 3.5 3 2.5 2 1.5 1.5 1.9% Valacyclovir Group (N=743) 3.6% Control Group (N=741) Corey et al, NEJM 24; 35:11-2 Genital HPV 12
HPV Highlights The HPV Family Best uses for HPV tests HPV vaccine who and when Dermal HPVs Common skin warts (~6 types) Mucosal HPVs (~4 types) Low-risk wart types High-risk cancer types Incidence of Cervical HPV Detection in Women From the Time of Sexual Debut 7% 6% 5% 4% 3% 2% 1% % Cervical HPV Detection 6 12 18 24 3 36 42 48 Time since first intercourse (mo) Collins S et al. Br J Obstet Gynecol. 22;19(1):96-98. Clearance of Cervical HPV Infections in Young Women Within 2 Years Percentage HPV Infected 1 8 6 4 2 3 6 9 12 15 18 21 24 Time from HPV infection (mo) Brown DR et al. J Infect Dis. 25;191(2):182-192. 13
Stages of Cancer Progression Natural History of HPV and Cervical Cancer Over the Lifespan Wright TC Jr, Schiffman M. N Engl J Med. 23;348(6):489-49. Reprinted with permission from Massachusetts Medical Society. Schiffman M, Castle PE. N Engl J Med. 25;353(2):211-214. Reprinted with permission from Massachusetts Medical Society. The HPV DNA Test Only test FDA-cleared: Digene (Qiagen) Hybrid Capture II RNA probe cocktail to 13 high risk types*: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, & 68 Provides positive or negative result Which patient are you most likely to test for HPV? A. 21-year-old woman in a new relationship who wants to get the HPV vaccine B. 28-year-old woman with ASC-US Pap result C. 34-year-old woman with LSIL Pap D. 45-year-old woman previously treated for cervical dysplasia E. None of the above * High risk HPV test 14
How Should Get an HPV Test? FDA-cleared for: Triage of ASC-US Adjunct screening in women age 3 and over Supported by research for F/U of: No CIN on colpo (ASC-H, LSIL, ASC-US/HPV+) -- 12 mo CIN 1 on colpo -- 12 mo Initial w/u of AGC; subsequent w/u of AGC w/ neg colpo - -6& 12 mo Post treatment CIN 2/3 -- 6-12 mo www.asccp.org NO ROLE for HPV DNA Testing Screening in women under 3 Diagnosis of genital warts Testing in males Triage of ASC-H, LSIL or higher grade lesions Before or after vaccination Screening STD patients or their partners HPV Virus-Like Particles (VLPs) Current HPV Vaccines L1 major capsid protein synthesized in yeast or insect cells assembles into structures resembling whole virus Manufacturer Product VLP types Antigen source Adjuvant Timing Target groups FDA clearance Quadrivalent Merck Gardasil 6, 11, 16, 18 Yeast Alum, 2, 6 mo Females 9-26 y (Males) June 26 Bivalent GSK Cervarix 16, 18 Baculovirus ASO4, 1, 6 mo Females 1-55 y Expected 28 Image: Shi L et al. Clin Pharmacol Ther 27; 81(2): 259-264 Gardasil PI. GlaxoSmithKline press release. March 29, 27. 15
Percentage of Worldwide Cervical Cancers Attributed to Different HPV Types Cumulative % 53.5 7.7 77.4 8.3 82.9 85.2 87.4 88.8 9.2 91.4 92.4 93.1 93.7 94.2 94.5 Quadrivalent HPV Vaccine Efficacy Clinical End Point CIN 2/3 or AIS Condyloma VIN 2/3 or VaIN 2/3 Per Protocol 98% 1% 1% ITT HPV 16/18- Related 44% 76% 62% ITT All HPV- Related 17% 51% 26% Roden R, Wu TC. Nat Rev Cancer. 26;6(1):753-763. Reprinted with permission from Nature Publishing Group. Future II Study Group. N Engl J Med. 27;356(19):1915-1927. Garland SM et al. N Engl J Med. 27;356(19):1928-1943. Anti-HPV 16 cria Geometric Mean Titer (mmu/ml) Anti-HPV 16 Titers Through 3.5 Years Postdose 3 3 2 1 1 1 1 Vaccination HPV 16 L1 VLP vaccine Placebo recipients previously infected with HPV 16 7 12 18 3 42 48 Month Since Enrollment Fever Nausea Vaccine-Related Experiences Injection Site 1-5 d Post-dose Pain Swelling Erythema Pruritus Systemic 1-15 d Post-dose Vaccine 83.9% 25.4% 24.6% 3.1% Vaccine 1.3% 4.2% Dizziness* 2.8% * Recommend observation 15 minutes Placebo (Alum) 75.4% 15.8% 18.4% 2.8% Placebo 8.6% 4.1% 2.6% Placebo (Saline) 48.6% 7.3% 12.1%.6% Mao C et al. Obstet Gynecol. 26;17(1):18-27. Gardasil Package Insert. 16
HPV Vaccines: Other Key Findings Duration of protection >5 years 1,2 No therapeutic value 3 Safe and immunogenic in males 4 Evidence for cross-protection against non-vaccine types 5,6 No role for HPV testing in vaccine program 1. Villa LL et al. Br J Cancer. 26;95(11):1459-1466. 2. Olsson SE et al. Vaccine. 27;25(26):4931-4939. 3. Hildesheim A et al. JAMA. 27;298(7):743-753. 4. Reisinger KS et al. Pediatr Infect Dis J. 27;26(3):21-29. 5. Harper DM et al. Lancet 26; 367:1247-1255. 6. Brown D. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL. Sept 17-2, 27. Which patient would you most strongly recommend the HPV vaccine? A. 18-year-old sexually active female college student B. 12-year-old female prior to sexual debut C. 15-year-old male prior to sexual debut D. 24-year-old female with history of cervical dysplasia E. None of the above Who Should Get an HPV Vaccine? Routine vaccination of females ages 11-12 years (as young as age 9 years) Catch-up vaccination for females 13-26 years Can by given despite history of abnormal Pap, HPV, genital warts Not recommended in pregnancy Contraindications: allergy to yeast or other vaccine component, severe illness Thank You! No change in cervical cancer screening recommendations VAERS: www.vaers.hhs.gov or 8-822-7967 Merck Pregnancy registry: 8-986-8999 MMWR. 27;56(RR-2):1-26. 17