Clinical Pearls Sexually Transmitted Infections March 8, 2014 Michael F. Rein, MD, MACP, FIDSA Professor Emeritus of Medicine Harrison Distinguished Educator University of Virginia Dr. Rein has no conflicts of interest to declare.
Preliminary pearl Management of STI always involves consideration of more than one individual: source or spread cases
Case 1 A 23 year-old woman is entering into a new heterosexual relationship and has been asked by her intended to be evaluated for genital herpes. She has had only penile-vaginal intercourse, six prior sexual partners, and no history of genital or orolabial lesions. She presents having obtained type-specific HSV serology which is positive for HSV-1 and negative for HSV-2, asking for guidance.
Question 1: What can you tell her regarding possible genital herpetic infection? 1. Nothing 2. Genital herpes is very unlikely but is possible 3. She probably has orolabial herpes acquired as a baby and should be careful about felatio 4. She has genital herpes
Herpes Simplex Types 1 and 2 DNA viruses Differ in DNA content Share many antigens but several are unique Glycoprotein G Cross-protection is incomplete
HSV-2 seroprevalence: men and women (95% confidence intervals rounded off) NHANES 1999-2004 2005-2010 14-19 yo 1.0% (1-2) 1.2% (1-2) 20-29 yo 10.6% (8-12) 9.9% (9-11) 30-39 yo 22.1% (20-24) 19.3% (17-21) 40-49 yo 26.3% (24-29) 25.6% (23-28) TOTAL 17.2% (17-19) 16.7% (15-17) Little change between these two time intervals Highest incidence in ages of sexual activity Beware of cohort effects Bradley H, et al: J Infect Dis 2014;209;325-33
HSV-1 Genital Infection Overall prevalence: at least 35% of genital herpes In newly acquired cases among young people: about 70% Ryder: Sex Transm Infect 2009, online; Pena KC, et al: J Clin Microbiol 2009; E publication, November 17, doi:10.1128/jcm.01336-09
Why do we expect to see more genital HSV-1? More oral sex, and this among younger people Less condom use during oral sex Fewer very young people experiencing nonvenereal acquisition and therefore first exposed sexually Less crowding Better hygiene More care regarding people with known orolabial HSV and babies (Aunt Edna)
HSV-1 seroprevalnce in men and women (95% confidence intervals rounded off) NHANES: 1999-2004 2005-2010 14-19 yo: 39.0% (37-41) 30.1% (27-33) 20-29 yo: 54.4% (52-57) 49.5% (46-52) 30-39 yo: 63.5% (61-66) 61.8% (59-65) 40-49 yo: 65.3% (63-68) 63.6% (60-67) TOTAL 57.9% (56-60) 53.9% (52-56) Decrease in prevalence in presexual ages Overall prevalence of antibody is high Beware of cohort effects Bradley H, et al: J Infect Dis 2014;209;325-33
Answer 1 is correct. A person with HSV-1 antibody may have genital herpes. Given the high prevalence of genital HSV-1, such infection cannot be ruled out. Because of the high prevalence of nonvenereal HSV-1 infection, genital herpes cannot be ruled in on serological grounds alone.
Clinical Pearls HSV-1 is now the most commonly acquired genital herpes, so type-specific serology is often useless. A sexual history must include questions about oral (and anal) sex The only sexually transmitted condition one cannot acquire through oral sex is pregnant
Case 2 A 28 year-old man attends a sales conference in Las Vegas. On his last night there, he has unprotected penile-vaginal sex with a prostitute. The following night he has penile-vaginal and oral-insertive sex with his wife. Two days later he develops urethral discharge and dysuria, and you diagnose him with gonorrhea. He asks if you can provide him with medication to give to his wife.
Question 2: Should you provide the patient with medication for his wife 1. No (expedited patient therapy)? 2. You cannot do it, because it is not legal in Virginia 3. You will not do it, because data have shown that it is ineffective 4. Yes, in this particular case (maybe)
Four questions you should ask yourself about expedited therapy Does it work? Is it legal? Is it ethical? What are the downsides?
Does expedited patient therapy work?
EPT (slightly) Reduces Reinfection Rate in STD Clinic Baltimore STD Clinic October 2007-March 2009 1085 heterosexual patients, 50% male EPT for at least 1 partner Vs. 2111 patients January 2006-June 2007 Reinfection rate: With EPT: 2.1% Without EPT 3.4% Note: historical controls 2010 National STD Prevention Conference (NSTDP): Abstract P86. Presented March 10, 2010 17
The Effectiveness of Expedited Partner Treatment on Re-Infection Rates 20% 15% GONORRHEA P=.02 CHLAMYDIA P=.17 10% 5% 0% 11% 13% 11% 3% Usual Care EPT Usual Care EPT Golden M, et al. N Engl J Med 2005 Feb 17;352(7):676-85.
Is expedited patient therapy legal?
Expedited Rx - Politics House joint resolution No. 147 Offered: January 11, 2012 Patron: Mr. Herring Joint Commission on Health Care be directed to study options for implementing To complete its meetings by November 30, 2013 Submit findings and recommendations no later than the first day of the next regular session of the General Assembly for each year February 2, 2012: Laid on table by voice vote February 14, 2012: Left in Committee on Rules
Code of Virginia 54.1-3303 a practitioner may prescribe Schedule VI antibiotics and antiviral agents to other persons in close contact with a diagnosed patient Consistent with recommendations of the Centers for Disease Control and Prevention or the Department of Health bona fide practitioner-patient relationship.with the diagnosed patient in the practitioner's professional judgment, the practitioner deems there is urgency to begin treatment to prevent the transmission of a communicable disease met all requirements for the close contact except for the physical examination required such emergency treatment is necessary to prevent imminent risk of death, life-threatening illness, or serious disability. Individualize!!! Uhhhh: schedule VI antibiotics?????
Virginia Board of Pharmacy Guidance Document 110-08, 7/1/12 In Virginia all prescription drugs are categorized into schedules. Schedules I through V, for the most part, mirror the federal schedules. All prescription or legend drugs not included in Schedules II through V are placed in Schedule VI in Virginia and are also referred to as controlled drugs or substances within the Drug Control Act. This is sometimes confusing as the term controlled is usually applied only to drugs in Schedules II through V.
Is expedited patient therapy ethical?
Expedited therapy approved by CDC American Bar Association American Medical Association Society for Adolescent Health and Medicine American Academy of Pediatrics American College of Obstetrics and Gynecology American Congress of Obstetricians and Gynecologists
2012 Gonorrhea Therapy Recs Ceftriaxone 250 mg im plus: Azithromycin 1 gm po or Doxycycline 100 mg po twice daily for 7 days Even if chlamydia-negative Azithromycin preferred: Single dose so better compliance Less resistance than to doxycycline CDCP: MMWR 2012; 61:590-4
Gonococcal cephalosporin resistance Courtesy:KG Ghanem Combined effects of several chromosomal mutations NEJM 2012;366(6):485-7 Oral cephalosporin resistance documented in the U.S. MICs increasing to injectable cephalosporins Oral and injectable cephalosporin resistance documented in the Far East and Europe MMWR 2011 Jul 8;60(26):873-7
Recommended by CDCP for expedited therapy Cefixime 400 mg po plus: Azithromycin 1 gm po Note that this is not first-line therapy
Is expedited patient therapy ethical? CDC currently says (2012) that oral regimens should not be used to treat gonorrhea Do not give oral cefixime 400 mg po as a single dose Use ceftriaxone 250 mg im But EPT must use oral regimens Here s a less-effective regimen for your partner Does partner have a right to know why he/she is being treated? Does partner have a right to counseling, testing for other STI, and test of cure?
What are the downsides? Cannot ensure that partner actually got treated Split medication among multiple partners? Saved for future use? Sold on the street? Cannot evaluate partner for other STI Coprevalence Cannot provide counseling Cannot document adequate treatment Beware of β-lactam allergy
Correct answer: 4 EPT is legal, recommended by many, and moderately effective It may be appropriate in selected cases, e.g. when the partner absolutely cannot be evaluated
Clinical Pearls Providing medication (EPT) to a patient to give to a partner is permitted in Virginia. One should carefully individualize, and EPT should not be the default position. Some things that happen in Vegas do not, in fact, stay in Vegas.
Case 3 A 54 year old man is referred because he had a positive treponemal test (e.g. Bioplex IgG) and a negative RPR when attempting to donate blood. He has no past history of syphilis or treatment thereof. He was treated for gonorrhea while in the service 30 years previously, with resolution of his symptoms. Physical examination is normal.
Question 3: What is the next step 1. Repeat the Rapid Plasma Reagin in 3 months 2. Obtain a different nontreponemal test (e.g. VDRL) 3. Obtain a different treponemal test (e.g. TPPA) 4. No further workup is necessary
Uses of Tests for Syphilis Classical: Nontreponemal first, and if positive go on to treponemal Newer: Treponemal first, and if positive go on to nontreponemal for quantitation Followup on therapy: Nontreponemal only (must use same test throughout) RPR may yield higher titers than does VDRL Q3 months to fourfold drop (pick up 85% of successes) Annually to stable titer Ghanem KJ, et al: Sex Transm Infect 2007;83:97-101 34
Advantages of treponemal first More sensitive than nontreponemals (VDRL, RPR) in most stages of syphilis Not entirely true in primary syphilis More specific than nontreponemals But Bayes s theorem will still hurt you in a very low prevalence population: low positive predictive value Can be automated, reducing technician time and increasing throughput Marangoni A, et al: Clin Diagn Lab Immunol 2005;12:1231-4 Loeffelholz MJ, Binnicker MJ: J Clin Microbiol 2012;50:2-6
Disadvantages of treponemal first Confusion regarding approach to discrepant trep+/nontrep- tests Lower positive predictive value than when it follows reactive RPR (Bayes again) Currently higher cost in low-prevalence populations Use traditional approach in low-volume laboratories Stays positive after adequately treated infection Loeffelholz MJ, Binnicker MJ: J Clin Microbiol 2012;50:2-6
Treponemal +/ Nontreponemal - Early primary syphilis Prozone phenomenon Late syphilis Tabes Paresis Some cases of adequately treated early syphilis Lyme disease 37
The Prozone Phenomenon Not seen with treponemal tests Seen in ~2% of serologic tests Antibody excess in very high titers No lattice formation Especially in 2 syphilis So a cause of trep+/nontrep- Eliminated by automatically diluting out nonreactive RPRs Beware of private labs 38
Cross reactivity between syphilis treponemal tests and Lyme disease Lyme +/Treponemal +/ RPR- 1/10 10% (95% CI: 0.00-30.85) 1/25 4% (95% CI: 0.10-25.35), a new, treponemal test 6 cases: False-positive Lyme screens in syphilis (negative Lyme Western Blot) Very small numbers: This space reserved for future data (?) Maragoni: J of Clin Lab Analysis 2009; 23 : 1 6; 2011 unpublished data on Syphilis Health Check ; Naesens R, et al: Acta Clin Belg 2011;66:58-59 39
Interpretation of the two tests Treponemal reactive + nontreponemal reactive = past or present syphilis Or: yaws, pinta, bejel Nontreponemal reactive + treponemal nonreactive = biological false positive No need to work up if an isolated finding Treponemal reactive + nontreponemal nonreactive =?????? 40
Treponemal +/Nontreponemal - Treat patients not lab tests Very careful history and physical examination Especially Hx of prior syphilis Hx of other STD Consult Reactor File (call Health Department) Consider different treponemal test (CDC) Evaluate sexual partners
UVA: Bioplex IgG ELISA 3 recombinant antigens: 15kDA 17kDA 47kDA Measured separately, then highest titer reported Warning: does not exclude syphilis within three weeks of acquisition Does not discriminate from yaws, pinta, (bejel)
Reverse serology at UVA 2012 Courtesy: Walter Olivera Syphilis Bioplex IgG 6473 Reactive 235 (3.6%) Equivocal 18 (0.3%) Reflex RPR 253 Reactive 85 (34%) Nonreactive 168 (66%) Previously reactive (i.e. treated) 28 TPPA 140 Reactive 78 (56%) Nonreactive 62 (44%)
Treponemal+/Nontreponemal- History of previous syphilis therapy: No further treatment indicated If high-risk behavior, may follow for increasing RPR titer No prior history of syphilis treatment Perform additional treponemal test (TP-PA, FTA-ABS) Preferably one based on a different antigen If positive, treat for late-latent syphilis If negative, consider yet another treponemal test CDC:MMWR 2008;57:872-5; Park IU, et al: J Infect Dis 2011;204:1297-304 44
Correct answer: 3 This is becoming a far more common scenario. Obtain a second treponemal test that uses a different antigen (e.g. TPPA vs recent ELISAs etc).
Clinical Pearl In the setting of an isolated finding of treponemal-reactive, nontreponemal-nonreactive, perform a different treponemal test (Virginia: usually TPPA) as the tiebreaker. If the second treponemal test is reactive, manage for syphilis of undetermined duration. If the second treponemal test is negative, syphilis is ruled out.
Case 4 An 18 year-old heterosexual man presents with a thin urethral discharge and mild dysuria for three days. You appropriately treat him with ceftriaxone/azithromycin. He promises that he will not have sex until he returns for reevaluation in 10 days. Surprisingly, his dual NAAT is negative for N. gonorrhoeae and C. trachomatis. When he returns, he says that he is only slightly better, and on examination, he still has a discharge.
Question 4: Your response Retreat with initial regimen and strongly advise abstinence and referral of sexual partners Retreat with double-dose regimen: ceftriaxone 500 mg im and azithromycin 2 gm po Retreat with metronidazole 2gm once and moxifloxacin 400 mg po qd for 10d No retreatment is indicated: this is not infectious
Nongonococcal Urethritis A syndrome with multiple causes Epidemiological treatment is important If you treat a patient with a particular regimen; insure that partner(s) receives the same treatment Don t rely too much on chlamydial tests Mycoplasma genitalium is a newly recognized and important pathogen 49
Etiologies of NGU Chlamydia trachomatis 25% Mycoplasma genitalium 10%-25% Ureaplasma urealyticum 16%-26% Trichomonas vaginalis 1%-16%(??) Enterobacteriaceae Herpes simplex Ideopathic 50
M. genitalium as a cause of NGU Median prevalence among men with nonchlamyidal NGU = 25% (10%-38%) Prevalence vs asymptomatic control group Statistically significant in 16/22 studies (73%) Odds ratios: 2.2-20.3 Dose-response relationship to severity Clinical resolution associated with elimination of organism Manhart LE, et al: Clin Infect Dis 2011;53(S3):S129-42 51
Mycoplasma genitalium in women Cervicitis (weaker) Endometritis (strong) Salpingitis (strong) Asymptomatic carriage Sweden: 6% US STD Clinics: 7% Britain, pregnant: 0.7% 52
Treatment of M genitalium urethritis Microbiological cures, pooled data Doxycycline 100 mg twice daily for 7-8 days Cured 88/212 (42%) of men Azithromycin, 1 gm Cured 371/466 (80%) of men Longer courses of azithromycin: no demonstrated advantage Manhart LE, et al: Clin Infect Dis 2011;53(S3):S129-42
Retreatment of M. genitalium Microbiologic failures after second treatment: Doxycycline Azithromycin 29% Azithromycin Doxycycline 70% Microbiologic failures after subsequent treatment with moxifloxacin: 12%-15% Zoler ML: Internal Medicine News 9/25/13 from Manhart LE: ISSTDR/IUASTDI 2013 54
M. genitalium induced resistance to macrolides 15 patients infected with M. genitalium Pretreatment isolates sensitive to azithromycin Failed treatment with azithromycin Persistent infection Organisms now resistant to azithromycin Sensitive to moxifloxacin but not some older fluoroquinolones Cured with moxifloxacin 400 mg daily by mouth for 10 days Do not use ciprofloxacin! Jensen, JS et al: Clin Infect Dis 2008;47:1546-53. Walker J, et al: Clin Infect Dis 2013;56:1094-1100 55
Empirical approach to NGU treatment failures Tetracycline/Doxycycline failure: Metronidazole/Tinidazole for trichomoniasis Azithromycin for mycoplasmas Azithromycin failure: Metronidazole/Tinidazole for trichomoniasis Moxifloxacin 400 mg orally daily for 10 days Also covers C. trachomatis Not FDA approved CDC: 2010 STD Rx Recs; Hamasuna et al: Sex Trans Infect 2011 56
We should treat all gonorrhea cases for coincident NGU Patients with gonorrhea may be carrying one of the other causes of NGU, like M. genitalium Use dual therapy even if negative for C. trachomatis If you don t use dual therapy: Beware of postgonococcal urethritis Patient treated for gonococcal urethritis with β-lactam Partial response or response with relapse in absence of reexposure Treat for agent of NGU Treat partners as well Dose of azithromycin 1 gm 57
Correct answer: 3 NGU treatment failures should be retreated with metronidazole 2gm po single dose and moxifloxacin (Avelox ) 400 mg po daily for 10 days. Be sure to treat partners as well.
Pearls Mycoplasma genitalium is an important cause of NGU and of genital disease in women Because of resistance, treatment-failure NGU should be retreated with (metronidazole and) moxifloxacin Gonorrhea, even if chlamydia-negative, should be treated with dual therapy