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									Developments in (all 30-50 or so)
STDs: Global Epidemiology and

      George Schmid, M.D., M.Sc.
             Dept of HIV
            WHO, Geneva
    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)


      Public health


              Divorce    Infectious diseases specialists
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?
What Is a Sexually Transmitted
What Is a Sexually Transmitted

  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
         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."


            Question #2

What proportion of cases of genital herpes
are acquired from persons who know they
              have herpes?
  Asymptomatic Individuals Are Very
• 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


                       Infection increasingly asymptomatic

Genital herpes
Human papillomavirus
                         Schmid et al. Lancet (in press)
         Question #3
How Do We Identify Asymptomatic

  This question applies to people with STIs
    and persons with any other infection
How Do We Identify Asymptomatic

            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
                              1. Abstinence
Effectiveness (high to low)
                              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

There are about 30-50 STIs, or disease
   syndromes that result from STIs
• Gonorrhea (Neisseria gonorrhoeae)
• Chlamydia (Chlamydia trachomatis)
• Syphilis (Treponema pallidum)
• Chancroid (Haemophilus ducreyi)
• Genital warts and cervical—mainly--cancer (human
• Genital herpes (herpes simplex virus)
• Hepatitis B (hepatitis B virus)
• 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
2. Late morbidity (continued)
   • Spread in body, e.g.,
      • 30% of individuals with untreated syphilis develop
           neurosyphilis, cardiovascular syphilis, or late benign
      • Disseminated gonococcal infection (DGI)
3. Adverse outcomes of pregnancy, i.e.,
   • Infertility
   • Affect the pregnancy, i.e., miscarriage, congenital
   • Affect the baby at delivery, e.g., genital herpes,
      Why Do We Care About STIs
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 CD4-
     antigen 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
                          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
          Disease                          Culture for HIV               PCR for HIV
                                            (Pos./Tested)               (Pos./Tested)
          Chancroid                           4/35 (11%)                     NT
          Chancroid                             2/7 (30%)                  6/7 (86%)
          Chancroid                                  NT                    2/6 (33%)
          Syphilis                                   NT                    1/2 (50%)
          Unknown                                    NT                    2/3 (67%)
          Genital herpes                             NT                    1/3 (33%)
          Genital herpes                         0/8 (0%)                25/26 (96%)
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                                        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
  Australia and New Zealand
      East Asia and Pacific
 South and South East Asia

         Sub-Saharan Africa                                              119

North Africa and Middle East             21

Latin America and Caribbean
              North America

            Western Europe              20

               CEE and NIS                    29

                               0       20         40    60   80   100   120    140

                                       Estimated prevalence (per 1000)
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
 Proportion of Men with Either
 Gonorrhea or Nongonococcal
Urethritis, by Type of Discharge
40                                                    GC
30                                                    NGU
        None         Clear        White      Yellow

Swartz SL et al. J Infect Dis 1978;138:445
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
   • 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

• 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 28-
     day period allows time for antibody to be
• “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
• 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
      Question #4

 HPV is a life-long infection

HSV-2 is a life-long infection
                Genital Herpes

• Genital herpes is common in the Industrialized
   • 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
   • 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

• 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           5-7 days                  One year

Inoculation First episode   Recurrent episodes

                                    “Shedding” of virus
  Clinical Differences Between Type 1
          and Type 2 Infections
• Type 1 infections cause about 15-30% of first-
  episode 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
• Culture
• PCR?
• Antigen detection tests
• Tzanck smear (about 60% sensitive)
    Therapy of First-Episode Genital
• 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
• 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
    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
• 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
• 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
• 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
   Genital Herpes--Management of Sex
• “Sex partners of patients who have genital herpes
  are likely to benefit from evaluation and
• 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.”

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:

Yes                  No

                    Test for:
            Diagnosis of Urethritis

• Objective evidence of a discharge, or evidence of
   • >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
   • 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
                Question #6

Three Months After Therapy, What Proportion
     of Young Women will Again Have:
    Bacterial Vaginosis   Chlamydia
    • 80%                 • 50%
    • 60%                 • 25%
    • 40%                 • 10%
    • 10%                 • 5%
        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
• 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

• Azithromycin, 1 gm, orally, once, or;
• Doxycycline, 100 mg, orally, twice a day, for 7 days.
 Follow-up of Patients with Chlamydia
• 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
     Diseases Characterized by Vaginal
•   Candidiasis
•   Trichomoniasis
•   Bacterial vaginosis
•   Others, e.g., desquamative inflammatory vaginitis
       Diagnosis of Trichomoniasis

• Wet mount of vaginal secretions (sensitivity, 50-
• 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
           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

            HBV Immunization Policy
           WHO European Region, 2004

Universal infant
Universal newborn
Universal adolescent
No universal HBV
HBV-The Major Primary Prevention

     Three dose series with good protection:
                One dose--50%
               Two doses--85%
              Three doses--95%
    Estimated Prevalence of Genital HPV
    Among Women and Men, Aged 15-49,
                   U.S. Genital Warts
                     1%    1.4 m
    Subclinical HPV by                 5 million
    colposcopy or cytology             Subclinical HPV by
                  14 million           amplified NA probes
     Prior infection, detected
     by antibody                             81 million

 34 million                                      No prior or current
Koutsky L. Am J                                  infection
Med 1997;102:3
    24-month Incidence and Duration of
HPV          Incidence    Median                   # resolved/
type            (%)    duration (mo)              #infected (%)
51*               8          7                      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?
            Question #2

What proportion of cases of genital herpes
are acquired from persons who know they
              have herpes?
                   Question #3

1. Screening
2. Partner notification
      Question #4

 HPV is a life-long infection

HSV-2 is a life-long infection
            Question #5

If I have gonorrhea, and I have sex with a
    woman, the chance of my giving her
           gonorrhea are about:
                Question #6

Three Months After Therapy, What Proportion
     of Young Women will Again Have:
    Bacterial Vaginosis   Chlamydia
    • 80%                 • 50%
    • 60%                 • 25%
    • 40%                 • 10%
    • 10%                 • 5%

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