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Developments in (all 30-50 or so) STDs: Global Epidemiology and Management George Schmid, M.D., M.Sc. Dept of HIV WHO, Geneva [email protected] Think About Training and Careers in Epidemiology and/or Public Health • The European training programme (Epiet) in epidemiology at the new European CDC, which is focusing on infectious diseases www.epiet.org (I think this is correct) • The American training programme (EIS programme) in epidemiology at CDC www.cdc.gov • World Health Organization www.who.org • Masters of science or public health degrees Behaviour (change) Lust STDs: Religion Public health Sex Divorce Infectious diseases specialists Risk! 10% Risk 10% Risk 2% Risk 8% Risk 12% Risk 20% Risk I Have Questions for You Question #1 How many of us in this room have, or have had, an STI? 90% 75% 60% 35% 25% What Is a Sexually Transmitted Infection? What Is a Sexually Transmitted Infection? An infection which is transmitted from one person to another through acts of sex and an infection for which we want to contact the sex partner to prevent transmission to other people Sexually Transmitted Infection=Sexually Transmitted Disease=Reproductive Tract Infection? "Dear, the doctor says I have bacterial vaginosis and you need to be treated." "Dear, the doctor says I have bacterial vaginosis and you need to be treated." "My lawyer will contact you tomorrow about the divorce." RTIs STIs STDs Question #2 What proportion of cases of genital herpes are acquired from persons who know they have herpes? 85% 60% 30% 10% Asymptomatic Individuals Are Very Important • With probably every STI, except ????, most people—male and female—are asymptomatic • Asymptomatic people probably are responsible for most disease transmission • We should make people aware of these facts Gonorrhea Chancroid Syphilis Infection increasingly asymptomatic Genital herpes Human papillomavirus Chlamydia Trichomonas Schmid et al. Lancet (in press) Question #3 How Do We Identify Asymptomatic People? This question applies to people with STIs and persons with any other infection How Do We Identify Asymptomatic People? 1. Screening 2. Partner notification Partner Notification • • How to do it? 1. Provider referral 2. Health authorities referral 3. Contract referral (make a "contract" with the patient to have partners into care in, e.g., 72 hours, or health authorities will contact them) Alternate approaches • Network approach • Give patient medication for partner (for only certain diseases, e.g., chlamydia, trichomonas) Prevention of STIs is Simple Effectiveness (high to low) 1. Abstinence 2. Mutual monogamy (with an uninfected partner) 3. Always use a condom 4. Monogamy 5. Limit number of sex partners 6. Limit number of low-quality sex partners 7. Have lots of sex with whomever you feel like and never use a condom STIs There are about 30-50 STIs, or disease syndromes that result from STIs STDs Bacteria • Gonorrhea (Neisseria gonorrhoeae) • Chlamydia (Chlamydia trachomatis) • Syphilis (Treponema pallidum) • Chancroid (Haemophilus ducreyi) Viruses • Genital warts and cervical—mainly--cancer (human papillomavirus) • Genital herpes (herpes simplex virus) • Hepatitis B (hepatitis B virus) Parasites • Trichomoniasis (Trichomonas vaginalis) Why Do We Care About STIs? Why Do We Care About STIs? 1. Acute morbidity 2. Late morbidity • Spread locally, e.g., • 10-40% of women with a gonococcal or chlamydial infection develop PID. Of women with one episode of PID: – 20% are infertile – Of those who become pregnant, 9% will have an ectopic pregnancy Why Do We Care About STIs (continued)? 2. Late morbidity (continued) • Spread in body, e.g., • 30% of individuals with untreated syphilis develop neurosyphilis, cardiovascular syphilis, or late benign syphilis • Disseminated gonococcal infection (DGI) 3. Adverse outcomes of pregnancy, i.e., • Infertility • Affect the pregnancy, i.e., miscarriage, congenital infection • Affect the baby at delivery, e.g., genital herpes, chlamydia Why Do We Care About STIs (continued)? 4. Cofactors for cancer • Cervical cancer (HPV, probably HSV) and anal and penile cancer (HPV) • Hepatic cancer (hepatitis B and hepatitis C) 5. Enhanced HIV transmission What Characterizes STIs? • Inflammation • Increased numbers of white blood cells, exudates • With some STIs, preferential recruitment of CD4antigen bearing cells • Breaks in mucosa or skin • Bleeding Evidence for the Enhancement of HIV Infection by STIs 1 Cross-sectional studies 2 Cohort studies 3 Biologic studies Cohort Study, Nairobi • 73 HIV-negative men with an STD • All men had had one act of sexual intercourse with a prostitute • The men were counseled, given condoms, told to avoid sex with prostitutes, and followed every 2 weeks for three months for HIV seroconversion • 85% of prostitutes were HIV-positive Cameron WD et al. Lancet 1989;2:403 Proportion of Men Developing HIV Infection After a Single Act of Sexual Intercourse Circumcised Uncircumcised Unstratified Urethritis Ulcer Urethritis Ulcer 13% 0% 7% (6*) 0% 43% (15) *Standard Error Attributable risk due to lack of circumcision and genital ulcer=98% Cameron WD et al. Lancet 1989;2:403 Presence of HIV in Ulcer Secretions Culture for HIV (Pos./Tested) 4/35 (11%) PCR for HIV (Pos./Tested) NT 2 2/7 (30%) 6/7 (86%) Chancroid 3 NT 2/6 (33%) Syphilis NT 1/2 (50%) Unknown NT 2/3 (67%) Genital herpes NT 1/3 (33%) 0/8 (0%) 25/26 (96%) Disease 1 Chancroid Chancroid Genital herpes 4 1 Kreiss J et al. J Infect Dis 1989;160:380 2 Plummer FA et al. J Infect Dis 1990;161:810 3 Mertz KJ et al. J Infect Dis 1998;178:1795 4 Schacker T et al. JAMA 1998;280:61 How Common Are STIs Globally? No one knows Estimated Incidence of STIs, by Continent Continent Estimated Incidence Western Europe 1-2% United States 2-3% Latin America 7-14% Southeast Asia 9-17% Sub-Saharan Africa 11-35% Delebatta G et al. Family Health International Estimated prevalence (per 1000) of STIs by region in 1999 Region 27 Australia and New Zealand 7 East Asia and Pacific 50 South and South East Asia 119 Sub-Saharan Africa 21 North Africa and Middle East 71 Latin America and Caribbean 19 North America 20 Western Europe 29 CEE and NIS 0 20 40 60 80 100 120 Estimated prevalence (per 1000) 140 Why Do People Get STIs? Anderson-May Equation Ro = $ c D Ro = reproductive rate $ = infectivity c = rate of partner change (sex, needle) D = duration of infectiousness Core group Number of partners Diseases and Syndromes 30-50 organisms or syndromes that are sexually transmitted Test! Proportion of Men with Either Gonorrhea or Nongonococcal Urethritis, by Type of Discharge 80 70 60 50 GC NGU 40 30 20 10 0 None Clear White Swartz SL et al. J Infect Dis 1978;138:445 Yellow Ability of Clinicians to Diagnose the Cause of a Genital Ulcer Disease Diagnostic Accuracy Chancroid 80% Syphilis 55% Genital herpes 22% Dangor Y et al. Sex Transm Dis 1990;17:184 STI Syndromes • No symptoms or signs • Urethral discharge/discomfort (urethritis) in males • N. gonorrhoeae • C. trachomatis • U. urealyticum • Testicular pain (epididymitis) • N. gonorrhoeae • C. trachomatis • Abdominal pain in women (pelvic inflammatory disease) • N. gonorrhoeae • C. trachomatis • Flora of bacterial vaginosis • ? Mycoplasma genitalium STI Syndromes (con’t) • Vaginal discharge/inflammation in women • Trichomonas vaginalis • Candida species (candidiasis) • Bacterial vaginosis • Genital “growths” • Human papillomavirus • Genital ulcers • Herpes simplex virus • Haemophilus ducreyi • Treponema pallidum STI Syndromes (con’t) • Inguinal adenopathy • Chlamydia trachomatis (LGV) • Haemophilus ducreyi Diseases Characterized by Genital Ulcers • • • • Chancroid Syphilis Genital herpes Other infectious causes of ulcers: • Epstein-Barr virus • Cytomegalovirus • Noninfectious causes, e.g. • Fixed drug eruption (tetracycline, laxatives commonly cause) • Trauma Diagnostic Tests for Genital Ulcers • History and physical exam! • Laboratory • Darkfield microscopy (syphilis) Exclude syphilis! • RPR syphilis serology • About 70% sensitive in primary syphilis (if negative today, repeat in one week) • Test for herpes • Culture, antigen tests, PCR Syphilis • Serology, with the screening RPR and a confirmatory, treponemal test (TPPA), is the mainstay of diagnosis • Works because the average incubation period for primary syphilis is 21 days and the average person waits 7 days before coming in—this 28day period allows time for antibody to be developed • “Strip” or “dip-stick” rapid tests, all based on treponemal antigen, are available Syphilis Therapy • For early syphilis*, a single dose of benzathine penicillin, 2.4 million units, intramuscularly Or • Procaine penicillin, 600,000 units daily intramuscularly for 10-14 days • See monthly for 3 months, then at 6 and 12 months for repeat RPR titers to document a four-fold decline, that is, cure. *Syphilis of one year’s duration or less All therapy guidance from: European STD Guidelines. Int J STD AIDS 2001;12S3. Question #4 HPV is a life-long infection True False HSV-2 is a life-long infection True False Genital Herpes • Genital herpes is common in the Industrialized World • About 20% of the adult population • It is a lifelong infection Prevalence of Antibody to HSV-2, Europe Smith J, Robinson J. J Infect Dis 2002; 186(S):S3 Genital Herpes • Genital herpes is very common in the Industrialized World • About 20% of the adult population • It is a lifelong infection “Facts” About Herpes Simplex Virus • Two types of herpes simplex virus, with about 50% DNA homology between the two. Clinically, they are separated by antibodies to the outer membrane glycoprotein • Type 1, which preferentially infects the oral area • Type 2, which "only" infects the reproductive tract • There is cross-protection between infection with the two types, which protects mostly against disease expression and not infection “Facts” About Herpes Simplex Virus (continued) • Terminology • Primary infection--the first time someone is infected with a herpes simplex virus • First-episode genital herpes—the first time someone has a recognized genital infection Time Line of Genital Herpes 7 days 7-21 days Inoculation First episode 5-7 days Recurrent episodes “Shedding” of virus One year Clinical Differences Between Type 1 and Type 2 Infections • Type 1 infections cause about 15-30% of firstepisode reproductive tract infections, but type 2 infections are infrequently acquired except through anogenital sex • Type 1 infections of the reproductive tract are milder than type 2 infections, and are less likely to recur Diagnostic Tests for Possible Genital Herpes • Culture • PCR? • Antigen detection tests • Tzanck smear (about 60% sensitive) Therapy of First-Episode Genital Herpes • Aciclovir, 200 mg, five times a day for 5 days • Famciclovir, 250 mg, three times a day for 5 days • Valaciclovir, 500 mg, twice a day for 5 days Counseling of First-Episode Genital Herpes • Patients should be counseled about: • The recurring nature of genital herpes • That many recurrent episodes are mild • That most cases of genital herpes are acquired from asymptomatic, or minimally symptomatic, cases • That sex should be avoided during prodromes or episodes, and that consistent condom use likely decreases transmission • That relatively normal lives can be led • That women who are infected may become pregnant and have children just as easily as women without a history of genital herpes Recurrent Episodes of Genital Herpes To treat recurrent episodes, or to suppress episodes? Treatment of Recurrent Episodes • Aciclovir, famaciclovir, or valaciclovir, in varying doses, for 5 days • Therapy must be started within 24 hours of the initial prodrome for there to be clinical effectiveness • So, patients should have either drug on hand, or, a prescription for drug Suppressive Therapy of Recurrent Episodes • Drugs • Aciclovir, 800 mg per day • Famciclovir, 250 mg, twice a day • Valaciclovir, 500 or 1000 mg a day (the lower dose is lnot as effective as the higher dose, particularly for those with high frequencies of recurrence, e.g., >10 recurrences/year) • Reduces frequency of recurrent episodes by 70-80%, and many patients have no episodes • Reduces, but does not eliminate, viral shedding Serologic Tests for Herpes Simplex Virus Type 2 • Serology has been available for many years • Does not reliably separate type 1 from type 2 infection, but is very good at identifying antibody to herpes simplex virus • Type 2 specific serology became commercially available in 1999 • One test on the market (HerpeSelectTM HSV-1 or HSV-2 IgG ELISA and HerpeSelectTM IgG HSV-1 or HSV-2 Immunoblot) • Sensitivity 80-98% (generally, >90%) but may achieve this 4-6 months after infection • Specificities >96% (Immunoblot may act as confirmation test) Genital Herpes--Management of Sex Partners* • “Sex partners of patients who have genital herpes are likely to benefit from evaluation and counseling.” • Symptomatic partners should be evaluated just as any symptomatic person • Asymptomatic partners should be questioned about a history of lesions, counseled to recognize outbreaks, and offered type-specific serology *This guidance is CDC guidance. European guidelines: “…it may be appropriate to offer to see partners to help with the counseling process.” Urethritis Symptoms: a discharge, or discomfort/pain when urinating Question #5 If I have gonorrhea, and I have sex with a woman, the chance of my giving her gonorrhea are about: 80% 60% 40% 15% Urethritis? Yes No Test for: Gonorrhea Chlamydia Diagnosis of Urethritis • Objective evidence of a discharge, or evidence of inflammation; • >5 WBC/oil immersion field on a Gram stain of urethral secretions, or; • A positive leukocyte esterase test on first-voided urine or; • >10 WBC per high power field on centrifuged, first-voided urine Only the Gram Stain Let’s You Separate Gonococcal from Nongonococcal Urethritis • High sensitivity for gonorrhea (>95%) • High specificity for gonorrhea (approaching 100%) Pathogenesis of Gonorrhea • Incubation period 3-5 days (in men); often uncertain in women • A single act of intercourse will result in transmission: • Infected male infects female, 40% • Infected female infects male, 25% Treatment of Gonorrhea • • • • Ceftriaxone, 250 mg, intramuscularly, once, or; Ciprofloxacin, 500 mg, orally, once *, or; Ofloxacin, 400 mg, orally, once; Spectinomycin, 2 gm, intramuscularly, once. *About 10% of cases in the UK are resistant, and there are known cases in eastern Europe Treatment of Gonorrhea (continued) Plus, if a chlamydial infection is not excluded: • Azithromycin, 1 gm, orally, once, or; • Doxycycline, 100 mg, orally, twice a day for 7 days Question #6 Three Months After Therapy, What Proportion of Young Women will Again Have: Bacterial Vaginosis • 80% • 60% • 40% • 10% Chlamydia • 50% • 25% • 10% • 5% Chlamydia Pathogenesis of Chlamydia • 48-hour life cycle, so that it grows very slowly in comparison to other bacteria (N. gonorrhoeae grows in 15 minutes) • The incubation period is, therefore, long (about two weeks) • How often a partner infects the other is uncertain, but if one person has chlamydia, the “typical” partner is infected in 40% of the time. Treatment of Chlamydia Recommended • Azithromycin, 1 gm, orally, once, or; • Doxycycline, 100 mg, orally, twice a day, for 7 days. Follow-up of Patients with Chlamydia (continued) • High rates of subsequent infection (up to 40%) occur in adolescent females • Consider advising all women with chlamydia infection to be rescreened 3-4 months after treatment. Diseases Characterized by Vaginal Discharge • • • • Candidiasis Trichomoniasis Bacterial vaginosis Others, e.g., desquamative inflammatory vaginitis Diagnosis of Trichomoniasis • Wet mount of vaginal secretions (sensitivity, 5070%) • Culture (sensitivity approaches 100% if appropriate media/culture conditions) • DNA probe (AffirmVPIIITM) from Becton Dickinson • PCR may be available from local laboratories Therapy of Trichomoniasis • Metronidazole, 2 gm, once, or; • Metronidazole, 500 mg, twice a day for 7 days • No follow-up needed, but there is antimicrobial resistance to metronidazole Bacterial Vaginosis An increasingly important disease Bacterial Vaginosis An increasingly important disease 1. Enhances HIV transmission 2. Causes PID 3. Causes post-procedure PID, e.g., after abortion, surgery Therapy of Bacterial Vaginosis • Metronidazole, 500 mg, orally, twice a day for 7 days, or; • Metronidazole gel, 0.75%, one applicator (5 gm), intravaginally, once a day for 5 days, or; • Clindamycin cream, 2%, one applicator (5 gm), intravaginally, once a day at bedtime for 7 days Effectiveness of Therapy 5-10 days 3-4 weeks Metronidazole, 2 g, once 84% 62% Metronidazole, 500 mg bid for 7 days 93 82 Clindamycin, 300 mg bid for 7 days 94 Metronidazole* gel bid for 5 days 81 71 Clindamycin cream qhs for 7 days 85 82 *qhs dose approved Joesoef et al. Clin Infect Dis Suppl 1995 and 1999. Pelvic Inflammatory Disease (PID) Diagnosis Remains a Problem What Causes PID? • • • • N. gonorrhoeae C. trachomatis Organisms of BV ?Mycoplasma genitalium Why Is PID Bad? Diagnostic Criteria for PID Minimum Criteria for Instituting Antimicrobial Therapy • Uterine/adnexal tenderness, or; • Cervical motion tenderness PPV=<65-90% (?) CDC Guidelines Do We Have Any Vaccines Against STIs? Hepatitis Hepatitis B Virus (HBV) • This IS a sexually transmitted disease • About ½ of cases in the industrialized world are acquired sexually The Happy Young European Border HBV Immunization Policy WHO European Region, 2004 Universal infant Universal newborn Universal adolescent No universal HBV immunization HBV-The Major Primary Prevention Strategy Immunize! Three dose series with good protection: One dose--50% Two doses--85% Three doses--95% HPV Estimated Prevalence of Genital HPV Among Women and Men, Aged 15-49, U.S. Genital Warts 1% 1.4 m Subclinical HPV by 4% colposcopy or cytology 10% 14 million Prior infection, detected by antibody 34 million Koutsky L. Am J Med 1997;102:3 60% 25% 5 million Subclinical HPV by amplified NA probes 81 million No prior or current infection 24-month Incidence and Duration of Infection HPV type 51* Incidence Median (%) duration (mo) 8 7 # resolved/ #infected (%) 29/36 (81) 66 7 6 26/28 (93) 16* 7 11 18/25 (72) 6 5 6 22/23 (96) 18* 4 12 11/17 (65) *High risk Ho GYF et al. N Engl J Med 1998;338:423 Thank you! Question #1 How many of us in this room have, or have had, an STI? 90% 75% 60% 35% 25% Question #2 What proportion of cases of genital herpes are acquired from persons who know they have herpes? 85% 60% 30% 10% Question #3 1. Screening 2. Partner notification Question #4 HPV is a life-long infection True False HSV-2 is a life-long infection True False Question #5 If I have gonorrhea, and I have sex with a woman, the chance of my giving her gonorrhea are about: 80% 60% 40% 15% Question #6 Three Months After Therapy, What Proportion of Young Women will Again Have: Bacterial Vaginosis • 80% • 60% • 40% • 10% Chlamydia • 50% • 25% • 10% • 5%