Internationell utblick STI/HIV i världen

Internationell utblick STI/HIV i världen Magnus Unemo, PhD, Assoc. Professor, Director Swedish Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology Örebro University Hospital, Sweden

Örebro University Hospital, Sweden Department of Laboratory Medicine (Head: Jan Forslid) WHO CC - staff involved when required - M Unemo (PhD; WHO CC Director) - D Golparian (MSc; WHO CC Scientific Officer) - S Jacobsson (PhD; WHO CC support) - R Hadad (MSc), M Hansen (BSc), M Larsson (BSc) - H Fredlund (MD, PhD), S Andersson (MD, PhD) +ECDC Reference Lab together with Public Health England for STIs in EU

WHO estimates: 357 million new cases of four curable STIs in adults (15-49 years), 2012 1 million new cases of STI/day Chlamydia ( 131 million), Gonorrhoea ( 78 million), Syphilis ( 6 million), Trichomoniasis ( 142 million) 3 Newman, Rowley, Vander Horn, Wijesooriya, Unemo, Low et al. Plos One. 2015

Solved? Challenges with STIs Remaining? - High incidence - Natural course Severe sequelae, incl. infertility and HIV transmission - Low number of etiologically diagnosed STIs - Suboptimal diagnostics, testing, case reporting, and treatment in many countries - High cost, especially as DALYs - Antimicrobial resistance (AMR) in N. gonorrhoeae, M. genitalium (MG), T. vaginalis, T. pallidum 4

WHO global estimates: 78 million new gonorrhoea cases in 2012 4.7 million 4.5 million 35.2 million 11.0 million 11.4 million 11.4 million 5 Newman, Rowley, Vander Horn, Wijesooriya, Unemo, Low et al. Plos One. 2015

- 52 995 cases in 28 countries - 16.9 per 100 000 population - 60% in UK; incidence varies based on testing and diagnostic assays

ÖREBRO LÄNS LANDSTING The Scream (Edvard Munch, 1893) 70 years Current options for empiric monotherapy Penicillins Tetracyclines Aminoglycosides Quinolones (ciprofloxacin, ofloxacin etc.) Macrolides (erythromycin, azithromycin) Only left Spectinomycin (Resistance selection! Not available!) Cephalosporins (ceftriaxone, cefixime) Unemo & Shafer. Clin Microbiol Rev. 2014

ÖREBRO LÄNS LANDSTING First NG Super Bug - H041 - High-level resistance to ceftriaxone (MIC=2-4 mg/l) and most antimicrobials (extensively-drug resistant; XDR) - Treatment failure of pharyngeal gonorrhoea (1g) Kyoto, Japan: Female sex worker

ÖREBRO LÄNS LANDSTING 1 st Superbug with high-level ceftriaxone resistance WHO 2012 ECDC for EU/EEA US CDC for USA August 2012 CEPHALOSPORIN RESISTANT NEISSERIA GONORRHOEAE PUBLIC HEALTH RESPONSE PLAN National Center for HIV/AIDS, Viral Hepatitis,STD,andTBPrevention Division of STDPrevention

ÖREBRO LÄNS LANDSTING WHO Global Gonococcal Antimicrobial Surveillance Programme (GASP) (Focal Centre: WHO Headquarter, Geneva) Europe (Magnus Unemo, Michelle Cole, ECDC) GISP (GISP, USA) Latin America (Jo-Anne Dillon, Argentina) Africa (TBD) SE Asia (Manju Bala) Western Pacific (Monica Lahra)

ÖREBRO LÄNS LANDSTING Future treatment of gonorrhoea? 1. Increased doses of ceftriaxone Limited time period (based on the MICs of N. gonorrhoeae Superbugs, pharmacodynamics and resistance emergence)! 2. Dual antimicrobial therapy Already introduced first-line (when susceptibility unknown) i) Ceftriaxone 250 mg + Azithromycin 1 g (USA 1 +Canada) ii) Ceftriaxone 500 mg + Azithromycin 1 g (UK 2 +Australia) iii) Ceftriaxone 500 mg + Azithromycin 2 g (Europe) 3 - Empirical treatment eradicating also Chlamydia 1 CDC. MMWR. 2010, 2012 and 2014 2 Bignell & Fitzgerald. Int J STD AIDS. 2011 3 Bignell & Unemo. Int J STD AIDS. 2013

ÖREBRO LÄNS LANDSTING Future treatment of gonorrhoea? 1. Increased doses of ceftriaxone Limited time period (based on the MICs of N. gonorrhoeae Superbugs, pharmacodynamics and resistance emergence)! 2. Dual antimicrobial therapy Already introduced first-line (when susceptibility unknown) Effective for how long? i) Ceftriaxone 250 mg + Azithromycin 1 g (USA 1 +Canada) 1. ii) Already Ceftriaxone resistance 500 mg + Azithromycin to both antimicrobials 1 g (UK 2 +Australia) 2. iii) Too Ceftriaxone expensive 500 mg for + wide Azithromycin use in 2 less-resourced g (Europe) 3 - settings Empirical treatment eradicating also Chlamydia 3. First global treatment failure recently verified! 1 CDC. MMWR. 2010, 2012 and 2014 2 Bignell & Fitzgerald. Int J STD AIDS. 2011 3 Bignell & Unemo. Int J STD AIDS. 2013

ÖREBRO LÄNS LANDSTING FIRST FAILURE GLOBALLY OF DUAL ANTIMICROBIAL THERAPY IN TREATMENT OF GONORRHEA Fifer H, Golparian D, Natarajan U, Alexander S, Hughes G, Jones L, and Unemo M New Engl J Med. 2016 - Heterosexual male with pharyngeal gonorrhoea in UK, but infected in Japan - XDR strain: Resistant to ceftriaxone, cefixime, azithromycin, penicillins, tetracyclines, and fluoroquinolones, but susceptible to spectinomycin

WHO estimates: 131 million new cases of urogenital chlamydia in adults in 2012 9 million 11 million 61 million 25 million 14 million 12 million 19 Newman, et al. Plos One. 2015

Reported rates of chlamydia in EU/EEA, 2013-384 555 cases in 26 countries - 182 per 100 000 population - Four countries (DK, NO, SE and UK) 83% of all cases test and use effective methods! - Large variation in reported cases across Europe

(lymphogranuloma venereum)

C. trachomatis (CT) Int J STD AIDS. 2015 (http://www.iusti.org/regions/europe/euroguidelines.htm)

Recommended treatment for uncomplicated anogenital C. trachomatis infections - Doxycycline 100 mg 1 orally twice daily, 7 days (preferred if rectal CT, where clearly better) - Azithromycin 1 g 1 orally (test of cure if rectal CT) When concomitant M. genitalium infection: Azithromycin 500 mg 1 day 1 plus 250 mg 1 day 2-5 Lymphogranuloma venereum (LGV): Doxycycline 100 mg 1 orally twice daily, 21 days Lanjouw et al. Int J STD AIDS. 2015

WHO estimates: 5.6 million new cases of syphilis in adults in 2012 0.4 million 0.5 million 1.0 million 0.9 million 0.9 million 1.8 million 29 Newman, et al. Plos One. 2015

- 22 237 cases in 29 countries - 5.4 per 100 000 population - 63% of all cases from UK, GE, RO, and ES

JEADV. 2014

Treatment of early syphilis (primary, secondary, early latent ; 1 years) First line (also in pregnancy): Benzathine penicillin G 2.4 million units intramuscularly (IM) once Second line (when penicillin allergy or parenteral treatment refused): Doxycycline 200 mg twice daily orally for 14 days (NOT in pregnancy) OR Azithromycin 2 g once orally Janier et al. JEADV. 2014

M. genitalium in males - M. genitalium accepted as an STI, but not yet surveyed by WHO or ECDC - Male acute NGU - 14% MG+ (median) in NGU cases - 20% MG+ (median) in NCNGU cases - Treatment failure results in persisting disease - Persisting/cronic NGU**** - 12-50% MG+ - Proctitis** - Detected in 5-12% of rectal swabs from men who have sex with men (MSM) - Some studies show correlates with symptoms

M. genitalium in females - Cervicitis*** (OR 1.66 (Lis et al. CID. 2015)) - Pelvic Inflammatory Disease (PID)*** - Same clinical picture as C. trachomatis - Likely explains 10-15% of PID - Infertility** Males and females: Increased HIV transmission***

M. genitalium population prevalence (United Kingdom) 4 NATSAL-3 Men 3,5 3 2,5 2 1,5 1 0,5 0 16-19 20-24 25-34 35-44 C. trachomatis M. genitalium N. gonorrhoeae Sonnenberg et al, 2015 and 2015

M. genitalium population prevalence (United Kingdom) 4 NATSAL-3 Women 3,5 3 2,5 2 1,5 1 0,5 0 16-19 20-24 25-34 35-44 C. trachomatis M. genitalium N. gonorrhoeae Sonnenberg et al, 2015 and 2015

Empiric treatment of MG infections First line (if macrolide resistance not detected): Azithromycin 500 mg 1 day one + 250 mg 1 the following four days (TOC >3 weeks) Resistance has rapidly increased! Jensen et al. JEADV. 2016; Unemo & Jensen. Nature Rev. In press

Empiric treatment of MG infections First line (if macrolide resistance not detected): Azithromycin 500 mg 1 day one + 250 mg 1 the following four days (TOC >3 weeks) Resistance has rapidly increased! Second line: Moxifloxacin 400 mg 1 daily in 7-10 days (TOC >3 weeks) Resistance increasing (now 3-15%), higher in Asia! Third line: Pristinamycin 1 g four times daily in 10 days: 90% cure rate as third line! (or doxycycline treating 30% of cases) Future options?: solithromycin, sitafloxacin, zoliflodacin, gepotidacin, lefamulin, (spectinomycin, omadacycline, eravacycline), dual antimicrobial therapy? Jensen et al. JEADV. 2016; Unemo & Jensen. Nature Rev. In press

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- Different epidemiology in different countries (heterosexuals, MSM, IDUs; domestic/imported) - Increase diagnostic testing in many settings, especially of hard-to-reach populations positive patients into care! - Increase availability of appropriate tests and increased use of 4 th generation tests (traditional and POC tests) - Increase availability of effective antiretrovirals and new drugs, and follow up (appropriate tests) 47

Women s Soccer World Cup 2015: Official Swedish slogan The clap = nickname of gonorrhoea since the 16th century

ÖREBRO LÄNS LANDSTING Acknowledgements - Jörgen Skov Jensen Statens Serum Institut, Copenhagen, Denmark - Gianfranco Spiteri European Centre for Disease Prevention and Control, Stockholm, Sweden WHO CC for Gonorrhoea and other STIs, Örebro University Hospital, Sweden: Magnus Unemo, Daniel Golparian, Susanne Jacobsson, Hans Fredlund, Sören Andersson, Ronza Hadad, Margareta Larsson, Marit Hansen