Sheldon Morris, M.D., M.P.H. of UC San Diego Antiviral Research Center, presents "Sexually Transmitted Infections Update" at AIDS Clinical Rounds

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current research, clinical practices and trends in HIV, HBV, HCV, TB
and other infectious diseases of global significance.
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AIDS CLINICAL ROUNDS

2. SEXUALLY TRANSMITTED
INFECTIONS UPDATE
Sheldon Morris MD MPH
Associate Clinical Professor
Div. of Infectious Diseases. Dept. of Medicine
Div. of Family Medicine, Dept. Family and Public Health
UC San Diego

3. Overview
• Recent changes in STI epidemiology,
pathogenesis, diagnosis and
treatment (pre-2014 Guidelines
release)

4. • Surgeon General of the United States of America, William
Stewart, said in 1967:
“The time has come to close the book on infectious
diseases. We have basically wiped out infection in the
United States.”

5. STI Morbidity United States
Complications of STIs
Fetal Wastage*
Low Birthweight*
Congenital Infection*
Upper Tract
Infection
Systemic Infection*
STIs
Infertility
Ectopic Pregnancy*
Chronic Pelvic Pain
HIV Infection*
Cancer *

6. !
BLOOD
No Bacterial
STIs
No herpesviruses
Favorable rectal
microbiota
!
!MUCOSA
!
!
TDF/ FTC
Activated
CD4+
(Targets) Resting
CD4+ (non-
targets)
Bacterial STIs
Herpesviruses
Unfavorable rectal
microbiota
!
HIV INOCULUM
TDF/ FTC
Intact Mucosal
Barrier Integrity
!
Impaired Mucosal
Barrier Integrity
!
Microbial Niche in HIV and STI Transmission

9. STD Screening

10. 1) STD Screening for Women
Sexually Active adolescents & up to age 25
Routine chlamydia and gonorrhea screening
Other STDs and HIV based on risk
Women over 25 years of age
STD/HIV testing based on risk
Pregnant women
Chlamydia
Gonorrhea (<25 years of age or risk)
HIV
Syphilis serology
HepBsAg
Hep C (if high risk)
CDC 2014 STD Tx Guidelines-Draft at www.cdc.gov/std/treatment

11. 2) STD Screening for MSM*
• HIV
• Syphilis
• Urine GC and CT
• Rectal GC and CT (receptive anal sex)
• Pharyngeal GC (receptive oral sex)
* At least annually, more frequent (3-6 months) if pt or their sex
partners have multiple partners, uses meth, or sexual
performance enhancing drugs
CDC 2014 (draft recommendations)
Other:
• Hepatitis B SAg (frequency not specified)
• Hep C if IDU or other risk factor
• (consider Hep A/B pre-vaccination serology)

12. Screening for HIV+ MSM
HCV : “HCV antibody tests should be serially
monitored, at least yearly and more frequently
depending on local circumstances (HCV prevalence,
incidence, resources, and other factors), to detect
conversion from HCV-antibody-negative to positive.”
Same recommendations as HIV- MSM plus:
Anal Cancer: Annual digital rectal exam may be
useful to detect early cancer, some centers perform
anal Pap and HRA for abnormal results (ASC-US or
worse)

13. 8) Testing after an STD infection
Proposed: Women who test positive for CT/GC, or
trichomonas should be rescreened three months following
treatment.
Men who test positive for chlamydia or gonorrhea should be
rescreened at three months after adequate therapy.
All patients with a bacterial STDs or trichomonas should be
tested for other STDs including CT/GC, syphilis, and HIV

14. Chlamydia
• Minor treatment guideline changes

15. Chlamydia—Rates by Sex, United States, 1992–
2012
NOTE: As of January 2000, all 50 states and the District of Columbia have regulations that require the reporting of chlamydia
cases.
2012-Fig 1. SR, Pg 9

17. Chlamydia—Prevalence Among Persons Aged 14–39 Years
by Sex, Race/Ethnicity, or Age Group, National Health and
Nutrition Examination Survey, 2005–2008
NOTE: Error bars indicate 95% confidence intervals.
2012-Fig 10. SR, Pg 13

18. Any syphilis, gonorrhea, chlamydia 28%
Rectal chlamydia
Rctal gonorrhea
Syphilis
10%
5%
7%
Serodiscordant partner 14%
Median Number of Partners 7
Any unprotected anal sex 51%
HIV Uninfected MSM Enrolled in CCTG 595 for Pre-exposure Prophylaxis
• Randomized controlled trial for text messaging to
improve adherence to pre-exposure prophylaxis
• 400 MSM and transgender at elevated risk of HIV
acqusition (Enrollment Now Closed)

19. Drug/Substance Use
Methamphetamine
Cocaine
Popper
Alcohol
Marijuana
Tobacco
17%
15%
55%
81%
51%
38%
Other Lifestyle factors
Erectile Dysfunction Drug 12%
Anabolic steroid 48%
Antibiotic Use 29%
Probiotic Use 42%
Prebiotic Use 66%
Rectal enema 68%
HIV Uninfected MSM Enrolled in CCTG 595 for Pre-exposure Prophylaxis

20. HIV Uninfected MSM Enrolled in CCTG 595 for Pre-exposure Prophylaxis
PERMANOVA of microbial
community structure from 16S
profiles
MDS ordination plots
-position samples 2D
dimensional representation of
the distances between samples
(small circles) and the centroids
(large circles) of the sample
groups
Sample distances were
computed using a Weighted
Rank Difference (WRD) with
2000 permutations.

21. HIV Uninfected MSM Enrolled in CCTG 595 for Pre-exposure Prophylaxis
PERMANOVA of microbial
community structure from 16S
profiles
MDS ordination plots
-position samples 2D
dimensional representation of
the distances between samples
(small circles) and the centroids
(large circles) of the sample
groups
Sample distances were
computed using a Weighted
Rank Difference (WRD) with
2000 permutations.

22. Chlamydia Treatment
• Uncomplicated genital/rectal/pharyngeal
• Azithromycin 1 gm PO
• Doxycycline 100 mg bid for 7 days
• Alternatives: Levofloxin/ofloxacin/erythromicin
• Pregnant women
• Azithromycin 1 gm PO
• Amoxicillin 500 mg tid for 7 days

23. Chlamydia Treatment
• Doxycycline 200 mg slow release OD for 7
days similar to 100 mg bid
• Doxycycline may be superior to
azithromycin for rectal chlamydia

24. Case Study
• 28 y.o. man with
2 day history of
dysuria and mild
urethral
discharge

25. Urethritis Gram Stain

27. Urethritis Treatment
• Gram stain available:
• GU: treat with standard regimen for GC + CT
• NGU: treat with standard CT regimen
• No gram stain available: treat for both GC + CT
• If diagnosis is equivocal, treatment based on level of
risk and likelihood of follow-up
• If response to treatment is inadequate, need to
evaluate for recurrent/persistent urethritis

28. Antimicrobial Drugs Used to Treat Gonorrhea Among
Participants, Gonococcal Isolate Surveillance Project (GISP),
1988–2013
“Other” includes no therapy (1.1%), azithromycin 2g (3.2%), and other less frequently used drugs (0.1%).
2012-Fig 28. SR, Pg 27

29. Case 1: Follow-up

31. Recurrent/Persistent Urethritis
• DDx Trichomonas; HSV; Ureaplasma;
Mycoplasma; non-infectious

32. Persistent NGU Treatment
Recommended regimens:
! Metronidazole 2 g orally in a single dose
OR
! Tinidazole 2 g orally in a single dose
PLUS
! Azithromycin 1 g orally in a single dose (if not
used for initial episode)
Moxifloxacin 400 mg PO x 7d effective for NGU
persistence or recurrence (M. genitalium)
Efficacy of AZ for M. genitalium declining

33. Gonorrhea
• Antimicrobial resistance
• New treatment guidelines

34. Gonorrhea—Rates, United States, 1941–2012
2012-Fig 11. SR, Pg 19

35. Antibiotic-Resistant Gonorrhea

37. Location of Participating Sentinel Sites and Regional Laboratories,
Gonococcal Isolate Surveillance Project (GISP), United States,
2012
*NOTE: Austin is a regional laboratory only.
2012-Fig 23. SR, Pg 25

38. Penicillin, Tetracycline, and Ciprofloxacin Resistance Among
Neisseria gonorrhoeae Isolates, Gonococcal Isolate Surveillance
Project (GISP), 2013
NOTE: PenR = penicillinase producing Neisseria gonorrhoeae and chromosomally mediated penicillin-
resistant N. gonorrhoeae; TetR = chromosomally and plasmid mediated tetracycline-resistant N.
gonorrhoeae; and QRNG = quinolone-resistant N. gonorrhoeae.
2012-Fig 27. SR, Pg 27

41. Neisseria gonorrhoeae — Distribution ofAzithromycin Minimum Inhibitory
Concentrations (MICs), Gonococcal Isolate Surveillance Project (GISP), 2009–2013
2012-Fig 26. SR, Pg 26

42. Gonorrhea Treatment
• Uncomplicated genital/rectal/pharyngeal in all
adults and pregnant women
• Ceftriaxone 250 mg IM PLUS
• Azithromycin 1 gm PO or
• Doxycycline 100 mg bid for 7 days
• Alternative : cefixime 400 mg PO PLUS azithro/
doxy or azithromycin 2 gm PO (only alternative for
pharyngeal)

43. Gonorrhea Dual Therapy
Uncomplicated Genital, Rectal,
or Pharyngeal Infections
Ceftriaxone 250 mg IM
in a single dose
Azithromycin
1 g orally
(preferred)
or
Doxycycline 100
mg BID x 7 days
PLUS*
• Regardless of CT test result
Proposed

44. What does dual therapy mean?
IM Ceftriaxone 250 mg + PO Azithromycin 1 gm administered on
the same day
ALTERNATIVE:
PO Cefixime 400 mg PO + PO Azithromycin 1 gm or
Doxycycline 100 mg BID x 7 days
CEPHALOSPORIN SEVERE ALLERGY:
IM Gentamicin 240 mg + PO Azithromycin 2gm OR
PO Gemifloxacin 320 mg + Azithromycin 2gm or

45. Who needs a test of cure?
• Patients with pharyngeal GC treated with an alternative
regimen, 14 days after Tx, using either culture or NAAT

46. Alternative Urogenital GC Regimens
! Non-comparative randomized trial in adults with urethral or cervical
gonorrhea
1. Gentamicin 240 mg IM + azithromycin 2 g PO, or
2. Gemifloxacin 320 mg PO + azithromycin 2 g PO
! Rationale for regimens
" Additive effect between gentamicin and azithromycin (in vitro)
" Gemifloxacin more active against GC with known ciprofloxacin resistance
" Drugs already available in U.S.
! Per-protocol efficacy:
" Gentamcin + AZ=100% (202/202)
" Gemifloxacin + AZ=99.5% (198/199)
! Nausea was common (27% and 37%), (3% and 7%) vomited <1hr
after administration
Kirkcaldy, CID 2014

47. Suspected GC Treatment Failure After
Recommended Dual Therapy
What do I do? (proposed)
CULTURE: if GC culture not available call your local health
department STD controller
REPEAT TREATMENT: Gemifloxacin 320 mg + AZ 2g
OR gentamicin 240 mg IM + AZ 2g
REPORT: To your local health department STD program within 24
hours, or call CDC 404-639-8659 for advice
TREAT PARTNERS: Within 60 days with same regimen as
patient receives
TEST OF CURE (TOC): Patient returns in 7-14 week for TOC
culture and NAAT
* If reinfection suspected instead of treatment failure, OK to repeat
treatment with CTX 250 + AZ 1g

48. Syphilis
Treponema pallidum
• Still going strong

49. Syphilis—Reported Cases by Stage of
Infection, United States, 1941–2013
2012-Fig 29. SR, Pg 32

50. Syphilis—Reported Cases by Stage of
Infection, United States, 2007–2013
2012-Fig 29. SR, Pg 32

51. Primary and Secondary Syphilis—Rates by County,
United States, 2012
NOTE: In 2012, 2,123 (67.6%) of 3,142 counties in the United States reported no cases of primary
and secondary syphilis.
2012-Fig 34. SR, Pg 34

56. Adults and Adolescents Living with Diagnosed HIV
Infection Ever Classified as Stage 3 (AIDS), by Sex,
1993–2011—United States and 6 Dependent Areas
Note. All displayed data have been statistically adjusted to account for reporting delays, but not for incomplete reporting.

58. Syphilis Treatment
Primary, Secondary & Early Latent:
! Benzathine penicillin G 2.4 million units IM in a single
dose
Late Latent and Unknown Duration:
! Benzathine Penicillin G 7.2 million units total, given as 3
doses of 2.4 million units each at 1 week intervals
Neurosyphilis:
! Aqueous Crystalline Penicillin G 18-24 million units IV
daily administered as 3-4 million IV q 4 hr for 10 -14 d
Only one dose of PCN Is recommended for early
syphilis in HIV-infected persons, extra doses not
needed

59. Syphilis Treatment
Primary, Secondary & Early Latent
Alternatives (non-pregnant penicillin-allergic adults):
! Doxycycline 100 mg po bid x 2 weeks
! Tetracycline 500 mg po qid x 2 weeks
! Ceftriaxone 1 g IV (or IM) qd x 10-14 d
! Azithromycin 2 g po in a single dose*
* Do NOT use azithromycin in MSM or pregnant women
In pregnancy, benzathine penicillin is the only
recommended therapy. No alternatives

60. Syphilis in HIV Infected MSM on ART: CCTG 592

61. Syphilis in HIV Infected MSM on ART: CCTG 592

62. Syphilis in HIV Infected MSM on ART: CCTG 592
No CMV
CMV Shedders

63. Syphilis in HIV Infected MSM on ART: CCTG 592

64. Syphilis Diagnostic Testing
• EIA first line serologic test for syphilis (e.g. TREP-
SURE) instead of RPR
• The TREP-SURE EIA uses specific recombinant
antigens from Treponema pallidum to detect IgG and
IgM in a qualitative, automated assay, which will
improve turnaround, sensitivity, and specificity.
• Any positive EIA will have reflex testing with
quantitative RPR for a titer within 24-48 hrs. (A
quantitative RPR should be ordered directly for all
known positive patients.)

66. Human Papillomavirus (HPV)
Genital Warts

67. Human Papillomavirus — Cervicovaginal Prevalence of Types 6, 11,
16, and 18 Among Women Aged 14–59 Years by Age Group and Time
Period, National Health and Nutrition Examination Survey, 2003–
2006 and 2007–2010
CDC STD Surveillance 2013

68. Genital Warts — Initial Visits to Physicians’
Offices, United States, 1966–2013
CDC STD Surveillance 2013

69. HPV Vaccine Recommendations
MMWR, 2014; Aug 29 (RR05)
* Irrespective of history of abnormal Pap, HPV
Population Recommendation
Gender Age
All Females 9-26 Routine vaccination with either
HPV4 or HPV2
All Males 9-21 Routine vaccination with HPV4
22-26 Permissive recommendation
HPV 4
MSM and
HIV+ Males
22-26 Routine vaccination with HPV 4

70. 10) HPV Vaccines
Gardasil PI. Cervarix PI.
Quadrivalent: Merck Gardasil®
• Types 6, 11, 16, 18
• Prevents warts, cervical cancer, anal cancer
• FDA-approved for females and males 9-26
yrs
• 3-dose series; $375
Bivalent: GSK Cervarix®
• Types 16, 18
• Prevents cervical cancer
• FDA-approved for females 10-25
yrs
• 3-dose series; $365
Nonavalent: Merck Gardasil9®
• Types 6, 11, 16, 18, 31, 33, 45, 52, 58
• FDA approved for females 9-26 yrs and
Males 9-15 yrs

71. HPV in HIV Infected MSM on ART: CCTG 592
High Risk* HPV, n (%)
Baseline Month 3 Month 6 Month 9 Month 12
Semen
7 (7.2)
Rectum
High Risk* 56 (45.2) 55 (50.5) 53 (47.8) 51 (47.7) 38 (39.6)
Genotype 16 15 (28.9) 19 (35.2) 11 (21.2) 14 (27.5) 11 (29.0)
Genotype 18/45 8 (15.4) 6 (11.1) 8 (15.4) 9 (17.7) 5 (13.2)
Throat 5 (3.9) 0 (0) 5 (4.6) 3 (2.8) 3 (3.1)
*mRNA from the E6/E7 oncogenes for 14 high-risk HPV types
(16/18/31/33/35/39/45/51/52/56/58/59/66/68) by Aptima

72. Predictors of High Risk* HPV at Baseline
HPV No HPV p AOR p
EBV shedding 25 (44.6) 10 (13.9) <0.01
3.56
(2.29-5.51)
<0.01
Mean Age 43.9 46.6 0.15
Plasma HIV 50-500 13 (23.2) 9 (12.5) 0.11
1.77
(1.11-2.84)
0.02
Mean CD4 count 531 647 <0.01
0.99
(0.99-1.00)
0.03
CMV shedding 34 (60.7) 34 (47.2) 0.13
Methamphetamine
use
10 (18.1) 7 (10.1) 0.20
2.44
(1.46-4.07)
<0.01
Median N (IQR) sex
partners past month
2 (0-6) 3 (1-5) 0.83
Median N (IQR)
anal sex acts
0 (0-3) 0 (0-2) 0.76
*mRNA from the E6/E7 oncogenes for 14 high-risk HPV types (16/18/31/33/35/39/45/51/52/56/58/59/66/68)

73. Days to Negative HR-HPV By EBV Shedding
P=0.004

74. Herpes Simplex Virus
• PCR for lesions
• Combination HIV/HSV prevention

75. Genital Herpes—Initial Visits to Physicians’Offices, United
States, 1966–2013
NOTE: The relative standard errors for genital herpes estimates of more than 100,000 range from 18% to 30%.
SOURCE: IMS Health, Integrated Promotional Services ™. IMS Health Report, 1966–2012.
2012-Fig 48. SR, Pg 45

76. Genital Warts
HSV-1 Prevalence NHANES
Bradley JID 2014

77. Herpes Simplex Virus Type 2 — SeroprevalenceAmong Non-Hispanic Whites and
Non- Hispanic Blacks by Sex andAge Group, National Health and Nutrition
Examination Surveys, 1988–1994, 1999–2002, 2003–2006, and 2007–2010
*Age-adjusted by using the 2000 U.S. Census civilian, non-institutionalized population aged 14-49 years as the standard.
NOTE: Error bars indicate 95% confidence intervals.
2012-Fig 49. SR, Pg 46

78. HSV NAATs
BD ProbeTec HSV 1 & 2 Qx Assay
# anogenital lesions in females
and males >16
EraGen Multicode-RTx HSV 1 & 2
# anogenital lesions in females >17
BioHelix HSV Assay
# Oral/anogenital lesions females
and males
# Indicates presence of HSV 1 or 2
# Not type specific

79. Genital Warts

80. Genital Herpes Suppression Rx
• Serodiscordant couples (in addition to consistent
condom use and avoidance of sexual activity during
recurrences)
• Persons who have multiple partners (including
MSM)
• Reduces the frequency of genital herpes
recurrences by 70%–80% in patients who have
frequent recurrences.
• Reassess yearly

81. Caprisa 040

82. Oral TDF in iPrEx
• 1,347 HSV-2-seronegative participants with follow-up, 125
(9.3%) had incident HSV-2 infection (5.9 per 100 py).

83. Other STDs
• Chancroid
• Mycoplasma genitalum
• Trichomonas/ vaginitis
• PID

84. Chancroid—Reported Cases by Year, United
States, 1981–2012
2012-Fig 44. SR, Pg 43

85. Trichomoniasis and Other Vaginal Infections—
Women—Initial Visits to Physicians’Offices, United
States, 1966–2012
NOTE: The relative standard errors for trichomoniasis estimates range from 16% to 27% and for other vaginitis estimates range from 8%
to 13%.
SOURCE: IMS Health, Integrated Promotional Services™, IMS Health Report, 1966–2012.
2012-Fig 50 SR, Pg 47

86. Questions…..