DÄ internationalArchive1-2/2016The Presentation, Diagnosis, and Treatment of Sexually Transmitted Infections

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The Presentation, Diagnosis, and Treatment of Sexually Transmitted Infections

Dtsch Arztebl Int 2016; 113(1-2): 11-22; DOI: 10.3238/arztebl.2016.0011

Wagenlehner, F M; Brockmeyer, N H; Discher, T; Friese, K; Wichelhaus, T A

Background: The reported incidence of sexually transmitted infections (STIs) in Germany is rising. For example, the number of new reported cases of syphilis rose from 3034 in 2010 to 4410 in 2012.

Methods: This review is based on pertinent articles retrieved by a selective search in MEDLINE, and on guidelines and systematic reviews from Germany and abroad.

Results: We discuss sexually transmitted infections presenting with genital, anal, perianal, or oral ulcers, urethritis, cervicitis, urethral or vaginal discharge, or genital warts. We also discuss sexually transmitted infection with HIV and the hepatitis C virus (HCV). Acquired sexually transmitted infections elevate the risk of transmission of other sexually transmitted infections; thus, patients presenting for the diagnosis or treatment of any kind of sexually transmitted infection should be evaluated for others as well. For most of these diseases, treatment of the patient’s sexual partner(s) is indicated. Diagnostic nucleic acid amplification techniques are over 90% sensitive and specific and are generally the best way to detect the responsible pathogen. Factors impeding effective treatment include antibiotic resistance (an increasing problem) and the late diagnosis of HIV and HCV infections.

Conclusion: Sexually transmitted infections are common around the world, and any such infection increases the patient’s risk of contracting other types of sexually transmitted infection. Molecular genetic diagnostic techniques should be made widely available.

LNSLNS

Sexually transmitted infections are caused by a wide variety of bacteria, viruses, and parasites that are communicated from one human being to another primarily by vaginal, anal, or oral sexual contact. Different sexually transmitted infections (STIs) can be present or be transmitted simultaneously, and the presence of any such infection increases the risk of contracting other types of STI. Sexually transmitted infections are often oligo- or asymptomatic.

According to the World Health Organization (WHO), sexually transmitted infections are one of the five types of disease for which adults around the world most commonly seek medical help (1). The current state of the data on the prevalence of sexually transmitted infections in Germany does not permit any reliable conclusions about infection rates, except for those of two diseases: human immunodeficiency virus (HIV) and syphilis (2).

Sexually transmitted infections can cause severe fetal and neonatal damage, genital neoplasia, and infertility. A number of diagnostic strategies and tests, of variable quality, are available for the individual pathogens.

The diagnostic and therapeutic algorithms can generally be tailored to the leading clinical manifestations (if the patient is symptomatic). Thus, sexually transmitted infections can usefully be classified by their presenting features, as follows:

  • Genital, anal, perianal, or oral ulcers
  • Urethral or vaginal discharge
  • Genital warts
  • HIV or hepatitis C virus (HCV) infection.

If the availability of diagnostic tests is limited, effective treatment can also be initiated without any testing on the basis of the clinical findings alone, if these are clearly typical of a particular sexually transmitted disease. Asymptomatic infections are common, however, and only detectable by testing.

Up to 90% of sexually transmitted infections are asymptomatic. The likelihood that an infection will be asymptomatic depends both on the site of infection and on the responsible pathogen. For example, the probability of asymptomatic rectal infection with C. trachomatis and N. gonorrhoeae is 85% in men who have sex with men (MSM) (e1). 30% of pregnant girls in Tanzania have an asymptomatic type 2 herpes simplex virus (HSV-2) infection (3). In the United States, about 85% of T. vaginalis infections in women are asymptomatic; so are 77% in men (4).

The treatment of sexually transmitted infections has the following objectives:

  • To cure the infection in the individual patient as rapidly as possible, and to eliminate contagiousness as rapidly as possible in order to interrupt the chain of transmission;
  • To prevent reinfection and recurrent infection.

The treatment of sexual partners is important as well. Bacterial infections and trichomoniasis can now be cured with systemic treatment (1, 5, 6). Viral infections due to HIV, HSV, and human papillomaviruses cannot be cured, but they can be weakened or modulated with systemic treatment (1, 5, 6).

Methods

We selectively searched the MEDLINE database for pertinent publications and guidelines (712, e2e4). Hepatitis B infections, scabies, pubic lice, cytomegalovirus infections, lymphogranuloma venereum, ulcus molle, and inguinal granuloma will not be discussed here.

Learning objectives

Readers of this article should be able to:

  • Recognize the clinical features of selected common sexually transmitted diseases
  • Apply the currently recommended diagnostic tests for these diseases
  • Know their appropriate treatment in the light of current antibiotic resistance rates.

Sexually transmitted infections presenting with genital, anal, perianal, or oral ulcers

Herpes simplex virus (HSV) infection

Infectious ulcers in the genito-anal region are commonly due to HSV. HSV-1 accounts for 20% of cases, HSV-2 for 80%. HSV infection is the most common sexually transmitted infection that causes ulcers. Herpes simplex virus persists in the human host for his or her entire lifetime. Painful vesicles may develop into erosions or ulcers that secrete a hyaline infectious fluid (Figure 1). The ulcers generally heal completely in two to three weeks. HSV infection can manifest itself initially with regional lymphadenopathy and fever; on the other hand, it can also be asymptomatic.

Acute herpes simplex virus infection in the area of the mons pubis
Acute herpes simplex virus infection in the area of the mons pubis
Figure 1
Acute herpes simplex virus infection in the area of the mons pubis

HSV infection can be transmitted by sexual contact (including oral sex) as well as perinatally from mother to child. Persons with an acute HSV-1 infection should refrain from unprotected oral sex. Unprotected sexual contact in the setting of HSV infection promotes the acquisition of HIV infection (odds ratio [OR] 1.7) (e5) and other sexually transmitted diseases. Moreover, studies have shown that HSV-2 infection triples the risk of HIV infection through unprotected sexual intercourse (e6). HSV infection is diagnosed by the analysis of vesicular fluid or genital secretions, generally with the aid of nucleic acid amplification techniques, which are the most sensitive method (over 95%) and nearly 100% specific (e7). The virus can also be revealed by antigen-detection techniques, but these are much less sensitive. Genital herpes infections are treated systemically with aciclovir, valaciclovir, or famciclovir; the dose depends on whether the episode is an initial infection or a recurrence, and on whether the patient is immunocompromised (Table). In patients who have HSV infections that recur four or more times a year, long-term viral suppression therapy with aciclovir, valaciclovir, or famciclovir should be considered (13). The treatment of sexual partners may be indicated (5). Treatment during pregnancy is important (e8, e9, 14) (treatment recommendations of the German STI Society [Deutsche STI-Gesellschaft – Gesellschaft zur Förderung der Sexuellen Gesundheit, DSTIG]: www.dstig.de/literaturleitlinienlinks/sti-leitfaden.html).

The treatment of sexually transmitted diseases
The treatment of sexually transmitted diseases
Table
The treatment of sexually transmitted diseases

Treponema pallidum infection (syphilis)

Syphilis is caused by Treponema pallidum. Sentinel analysis in Germany revealed a fluctuating reported incidence of the disease in the range of 1.1 to 1.9 cases per 100 000 persons per year from 2003 to 2008 (2). There were 3034 reported cases in 2010, and 4410 in 2012 (7). Syphilis in clinical stage I, II, or III is called “early syphilis” for the first year after the date of infection and “late syphilis” at later times. Half of all infected persons develop a painless ulcer with an indurated edge (ulcus durum) after an average interval of three weeks; this heals in 4–6 weeks with or without treatment (Figure 2) (7). Painless lymphadenopathy develops regionally. Hematogenous spread (stage II; secondary syphilis) leads to systemic symptoms arising six weeks to six months later, including fever, myalgia, bone and joint pain, transaminase elevation, and, typically, a maculopapular rash (roseola syphilitica). Other, polymorphic types of rash (Figure 2) can arise through involvement of the mucous membranes (plaques muqueuses), the palms and soles (palmoplantar syphilid); intertriginous condylomata lata can be distinguished visually from condylomata acuminata by experienced clinicians (Figures 3b and c). Treponemes are present in these skin lesions, which can therefore transmit infection by contact (7). 75% of untreated patients have no further symptoms after the end of stage II (7), but 25% develop tertiary syphilis (stage III) in 12 months to 10 years (7). Stage III syphilis causes a wide variety of general medical, neurological, and psychiatric morbidity and may be life-threatening if untreated.

Primary infection and secondary stage of syphilis: ulcus durum on the upper lip; maculopapular facial rash
Primary infection and secondary stage of syphilis: ulcus durum on the upper lip; maculopapular facial rash
Figure 2
Primary infection and secondary stage of syphilis: ulcus durum on the upper lip; maculopapular facial rash

The pathogen is generally revealed serologically by antibody detection in the framework of the diagnostic algorithm. First, a pathogen-specific screening test is performed, e.g., a Treponema pallidum particle agglutination test (TPPA). If this test is positive, it is followed by a specific confirmation test employing a different antigen strategy, e.g, an enzyme-linked immunosorbent assay (ELISA). If this test is positive as well, the activity level of syphilis is assessed in a third stage of evaluation (e.g., cardiolipin antibodies or treponeme-specific IgM), in order to distinguish syphilis in need of treatment from residual seropositivity in inactive disease. With appropriate equipment, an experienced examiner can see Treponema pallidum directly on dark-field microscopy of vesicular fluid or genital secretions in primary syphilis (caution: the specimens are infectious). In Germany, all positive laboratory tests for syphilis must be reported anonymously to the Robert Koch Institute (the governmental infection control agency). If neurosyphilis is suspected, CSF should be obtained by lumbar puncture and submitted for analysis; this should also be done in any patient with suspected syphilis who is HIV-positive with severe immunodeficiency (< 200 CD4+ cells), or in whom the date of exposure is unknown (possible late syphilis) (7).

The disease is transmitted exclusively by direct contact with the genito-anal or oral mucosa (less commonly, the skin) of infected persons, i.e., by sexual contact. Intrauterine transmission is also possible. Syphilis cannot be transmitted by objects such as towels, toilet seats, etc., although transmission via “sex toys” is possible in certain situations. The spread of syphilis can be halted by timely diagnosis and rigorous treatment, with regular clinical and serologic monitoring of its effect; patients should be thoroughly informed of the diagnosis and its implications, and all of their sexual partners from the three months prior to the onset of the disease should be tested.

Penicillin is the drug of first choice for syphilis. Early syphilis is treated with a single injection of benzathine penicillin, 2.4 million IU i.m., while late syphilis is treated with three injections of the same drug at the same dose, one each on days 1, 8, and 15 (Table). Patients who are allergic to penicillin can be alternatively given doxycycline  100 mg p.o. b.i.d. for 14 days, or ceftriaxone 1–2 g i.v. for 10 days. The treatment of congenital syphilis will not be discussed here (e8). Treatment failure rates are high—6.9–22.4% in early syphilis, 19.4–31.1% in late syphilis, and 27.3–27.8% in neurosyphilis (7). Thus, all patients need rigorous clinical and serologic follow-up every 3 months for a year (2 years in HIV-positive or immunocompromised patients) (7). All patients with syphilis should be tested for other sexually transmitted diseases, including gonorrhea and HIV (6).

Sexually transmitted infections presenting with urethral or vaginal discharge

Urethritis

Urethritis can be of either infectious or non-infectious origin. It is often asymptomatic. If symptomatic, it generally presents with a mucopurulent or purulent discharge, dysuria, or itching. The main pathogens are Neisseria gonorrhoeae, Chlamydia trachomatis, and Mycoplasma genitalium (6, e4); rarer ones include Trichomonas vaginalis, Gardnerella vaginalis, Ureaplasma urealyticum, herpes simplex virus (HSV), and adenoviruses (6, e10).

The following clinical findings suggest the diagnosis of urethritis:

  • Mucopurulent or purulent urethral discharge (Figure 4)
  • ≥ 2 leukocytes in a smear of the urethral discharge under 1000x magnification
  • ≥ 10 leukocytes in the sediment of 3 mL of early-stream urine under 400x magnification
  • A positive leukocyte esterase test of early-stream urine.
Purulent urethral discharge in gonorrheal urethritis
Purulent urethral discharge in gonorrheal urethritis
Figure 4
Purulent urethral discharge in gonorrheal urethritis

Mere visual inspection of the discharge is inadequate for a reliable etiologic diagnosis. Gram staining of the urethral discharge should be performed for rapid diagnosis; in men, Gram staining is 95% sensitive and 99.9% specific (10, 15).

Patients are treated empirically with antibiotics covering N. gonorrhoeae and C. trachomatis (Table) (7). In Germany, N. gonorrhoeae has high rates of resistance to penicillin (80%) and fluoroquinolones (74%) (1619). Orally administered cefixime has been repeatedly reported to have a high rate of treatment failure and is therefore not recommended for first-line empiric treatment (6, 9). If antibiotic treatment brings no improvement, additional evaluation for T. vaginalis (microscopy, nucleic acid test [NAT]) and M. genitalium (NAT) should be considered. Doxycycline treatment is generally ineffective against urethritis due to M. genitalium (6, 20, e11). Treatment with a single dose of azithromycin 1 g p.o. is associated with the development of macrolide resistance; thus, the currently recommended treatment of urethritis due to M. genitalium consists of one dose of azithromycin 500 mg p.o., followed by azithromycin 250 mg p.o. q.d. for 7 days (7, 20). If this is ineffective, moxifloxacin 400 mg p.o. q.d. should be given for 10 to 14 days (7, 20). Insufficient data are available on the efficacy of other fluoroquinolones, such as ciprofloxacin or levofloxacin. The clinical significance of other Mycoplasma species and of Ureaplasma species is currently debated (21).

Patients with diagnosed urethritis should be tested for other sexually transmitted infections, including HIV and syphilis (6).

The patient’s sexual partner(s) of the past 60 days should be evaluated and, if necessary, treated. The patient should remain sexually abstinent until at least 7 days after the end of treatment.

A follow-up evaluation with NAT should be performed four weeks or more after the end of treatment to confirm the eradication of the infection.

Cervicitis

Cervicitis has two main diagnostic hallmarks:

  • A purulent or mucopurulent discharge that is visible in the endocervical canal or on an endocervical smear (generally termed “mucopurulent cervicitis” or simply “cervicitis”), and
  • Persistent endocervical bleeding, which can be easily induced by the gentle insertion of a swab in the cervix.

Either or both of these signs may be present. Cervicitis is often asymptomatic, but many affected women complain of an abnormal vaginal discharge or intermenstrual bleeding (e.g., after sexual intercourse).

The main pathogens are C. trachomatis and/or N. gonorrhoeae; rarer ones include T. vaginalis and HSV-2 (e12). Limited data suggest that M. genitalium can also cause cervicitis. In most cases of cervicitis, however, no pathogen is isolated (10).

Leukorrhea is defined as a vaginal discharge in which there are more than 10 leukocytes per high-power field under 400x magnification. This finding indicates cervicitis as long as there is no clinical evidence of infectious vaginitis. Because cervicitis can also be a sign of endometritis, women with newly diagnosed cervicitis should also be evaluated for a possible pelvic infection with C. trachomatis or N. gonorrhoeae. NAT is currently the most sensitive test for T. vaginalis (6).

The empiric treatment of cervicitis should be directed against C. trachomatis, and also against N. gonorrhoeae in patients at high risk, i.e., those with multiple sexual partners or a history of prior sexually transmitted infections (for the choice of antibiotic, see the treatment of urethritis, above). Women in whom cervicitis due to C. trachomatis and/or N. gonorrhoeae is diagnosed should also be tested for other sexually transmitted infections, including HIV and syphilis (6).

Trichomonas infection

In men, infection with Trichomonas vaginalis can present with the symptoms and signs of urethritis, epididymitis, or prostatitis; in women, it presents with a vaginal discharge that may be diffuse, ill-smelling, or yellowish-green. 70–85% of all infected persons, however, have minimal or no symptoms, and untreated asymptomatic infection can persist for months or years (e13). T. vaginalis infection elevates the risk of acquiring HIV by a factor of 2 to 3 (e14).

For many years immediate microscopy was the most common diagnostic test for Trichomonas infection, despite a low sensitivity of only 50% to 65% (22). NAT, developed recently, is 95% to 100% sensitive and specific (e15). In one study, the use of NAT increased the rate of positive diagnosis from 2.7% to 13.5% (22); thus, NAT is clearly indicated. In general, either a smear of urethral or vaginal origin or the patient’s urine is studied. The treatment is with nitroimidazoles (Table).

Persons infected with T. vaginalis should also be tested for other sexually transmitted diseases (e.g., chlamydia, gonococci, or human papillomaviruses [HPV]). A follow-up test after treatment is recommended to document the eradication of the infection (5). Sexual partners should be treated as well.

Sexually transmitted infections presenting with genital warts

Human papillomavirus infection

Human papillomaviruses (HPV) are divided into two types on the basis of their oncogenic potential. Low-risk varieties, such as HPV6 and HPV11, give rise to condylomata acuminata (genital warts) (Figure 3a, b); high-risk varieties, such as HPV16 and HPV18, cause neoplasia. The treatment of condylomata acuminata is difficult and often protracted. Recurrence rates of 6–60% after topical treatment, 18–77% after surgery, and 9–69% after surgical treatment have been described (23). Persistent HPV infection (possibly due to an underlying immunodeficiency) increases the risk of dysplasia and tumors. More than 99% of cervical carcinomas and more than 90% of anal carcinomas are HPV positive, and HPV can be demonstrated in up to 70% of penile, vulvar, and vaginal carcinomas (5). Up to 30% of carcinomas of the throat, and tonsillar carcinomas in particular, are caused by HPV (e16). Anal carcinoma is a central problem in HIV medicine today, as it is more common among HIV-positive men who have sex with men (70–100 per 100 000) (23, 24 e17). Genital warts should be treated locally with cryotherapy, trichloroacetic acid, or ablative techniques such as curettage. The surgical treatment of anogenital warts should be followed by adjuvant topical treatment with 5% imiquimod ointment for 8 weeks. Alternatives include podophyllotoxin, 5-fluoruracil and cyclosporine. Precancerous lesions and carcinomas should be treated according to the current guidelines (e18).

Various appearances and localizations of condylomatous warts
Various appearances and localizations of condylomatous warts
Figure 3
Various appearances and localizations of condylomatous warts

HIV and HCV infections

HIV infection

Of the estimated 80 000 persons with HIV in Germany today, roughly 90% acquired the infection through sexual contact (5, 25). Two-thirds are men who have sex with men (MSM). The incidence of HIV infection has risen slightly over the past 10 years. The highest number of new cases in Germany in a single year was 3525, in 2014. 780 of these cases were reported as having been caused by heterosexual transmission (HET); that was 182 more HET cases than had been reported the previous year (e16). If untreated, HIV infection progresses from the acute infection to the latency stage (2–10 years), the symptomatic stage, and death (Centers for Disease Control [CDC] classification). HIV-positive persons who receive timely and appropriate treatment, with good compliance, now have nearly the same life expectancy as HIV-negative persons (2630, e19). Late diagnosis, however, is still a common and serious problem: 1/3 of all persons with HIV in Germany were diagnosed only in a stage of advanced immunodeficiency (< 200 CD4/µL). This markedly worsens the clinical course and increases the risk of transmission (27, e20).

The opportunity to diagnose HIV arises when the patient has an acute HIV infection or suffers from symptoms that may be due to HIV, or from AIDS-defining symptoms or conditions. 50–90% of persons with acute HIV infection have an EBV or flu-like illness (EBV, Epstein-Barr virus), generally of brief duration, within 3–4 weeks of the exposure. Features that indicate a possible HIV infection include a history of possible HIV exposure, fever, rash, and a marked loss of helper T-cells (CD4+ lymphocytes). In persons with untreated HIV infection, the gradual loss of cellular immunocompetence causes atypical symptoms and signs (Box). HIV infection can often be suspected from the site, extent, and severity of an infection or condition of a possibly opportunistic type, as well as from its tendency to recur or its resistance to standard treatment. It is important for the physician and the patient to have an open, unprejudiced discussion of the patient’s sexual orientation and practices (5).

HIV testing
HIV testing
Box
HIV testing

The risk of transmission depends on the concentration of the virus (HIV), the particular sexual practices involved, and any concomitant infection with other sexually transmitted diseases (31, 32, e20, e21).

The concentration of virus particles is highest at the time of primary infection and in the stage of advanced immunodeficiency (106–107 copies/mL in the blood). The higher the viral burden, the higher the risk of transmission by sexual contact; HIV transmission is unlikely if the HIV-positive individual has a consistently low viral count (less than 50 copies/mL) and no other concomitant sexually transmitted diseases (e22). Among all sexual practices, being the receptive partner in unprotected anal intercourse confers the highest risk of contracting HIV—up to 1.4%, depending on the viral count of the HIV-positive person (e23).

The risk of HIV transmission is elevated by a factor of 3 to 10 by the concomitant presence of a florid sexually transmitted infection (33, e23, e24). Such infections are common among persons with HIV (13–16%) (33, e22). Sexually transmitted diseases take a more complicated course in HIV-positive persons than in HIV-negative persons; they also induce a rise in viral counts and progression of the HIV disease (34, e3).

The risk of HIV transmission can be lessened by:

  • Rigorous treatment of sexually transmitted infections (42%)
  • Condoms (85%)
  • Antiretroviral therapy (ART) (96%)
  • ART and condoms (99.2%) (e23)
  • Pre-exposure prophylaxis of HIV-negative sexual partners (86%) (5, 6).

The CDC stage of HIV depends on the clinical findings and the helper cell count. The key surrogate markers for the assessment of prognosis and for the monitoring of treatment are:

  • The helper cell count (CD4+/µL). The lower the count, the more severe the cellular immunodeficiency and the higher the risk of AIDS and death.
  • The concentration of virus particles in the blood (viral count in RNA copies/mL). The higher the viral count, the more rapid the progression of disease and the higher the risk of transmission.

Antiretroviral therapy should be offered to the patient as soon as HIV is diagnosed; this is the recommendation of the WHO (35) as well as of the American HIV guidelines (e25). The German and Austrian guidelines are now being revised (e2).

Early treatment, with good compliance, suppresses the virus completely and gives HIV-positive persons a life expectancy comparable to that of HIV-negative persons. The early initiation of treatment saves money compared to later initiation (e23), as well as being an effective preventive measure against disease transmission (36).

HCV infection

Hepatitis C virus (HCV) infection is not a typical sexually transmitted disease. Nonetheless, HIV-infected men who have sex with men and who have many sexual partners, use sexually stimulating drugs, and engage in traumatizing sexual practices have a 17.8% risk of contracting HCV, compared to 0.4% among HIV-negative persons (5, 37, e26). Any man who has sex with men and in whom an HCV infection is newly diagnosed should be evaluated for other sexually transmitted infections, including HIV and syphilis. Double and triple infections are common (up to 15%).

Persons infected with HIV should undergo annual screening tests for HCV (with anti-HCV antibody and HCV-RNA tests). There is no vaccine against HCV, and 80% of HCV infections are chronic (e27, e28). The new, directly acting drugs against HCV enable interferon-free treatment for all types of HCV (e28, e29). As a rule, cure is attained in over 90% of treated patients within 12 weeks (38). Persons co-infected with HIV and HCV are at increased risk of hepatic cirrhosis and should be given antiviral therapy for HCV infection, just as is recommended for HCV mono-infection (e28, e29).

Conflict of interest statement

Prof. Wagenlehner has served as a paid consultant for Astellas, Bionorica Cubist, Galenus, Leo-Pharma, Merlion, OM-Pharma, Pierre Fabre, Perell Research, Rosen Pharma, and Zambon. He has received payment for presenting at continuing medical education events from Astellas, Bionorica Cubist, Galenus, Leo-Pharma, Merlion, OM-Pharma, Pierre Fabre, Rosen Pharma, and Zambon. He has also received payment for carrying out clinical trials on behalf of Astellas, Bionorica, Calixa, Cerexa, Cubist, The German Research Foundation (Deutsche Forschungsgemeinschaft), the European Association of Urology, Galenus, The Hessen State Ministry of Higher Education, Research and the Arts, Merlion, OM-Pharma, Rosen Pharma, and Zambon.

Prof. Brockmeyer has recieved reimbursement of conference participation fees and travel and accommodation costs from Gilead, Jansen, and MSD. He has received payment for carrying out clinical trials on behalf of Gilead, MSD, and Jansen.

Prof. Wichelhaus has served as a paid consultant for Teutopharma. He has received payment for preparing continuing medical education events from Pfizer, Bayer, Biomerieux, and Gilead.

Dr. Discher has served as a paid consultant for Gilead, Abbvie, and Roche. He has recieved reimbursement of conference participation fees and travel and accommodation costs, as well as payment for preparing continuing medical education events, from BMS, Gilead, MSD, Roche, Abbvie, and Janssen.

Prof. Friese states that he has no conflict of interest.

Manuscript submitted on 13 January 2015, revised version accepted on
17 November 2015.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. Florian M.E. Wagenlehner
Klinik und Poliklinik für Urologie, Kinderurologie und Andrologie
Universitätsklinikum Giessen und Marburg GmbH, Standort Giessen
Justus-Liebig-Universität Giessen
Rudolf-Buchheim-Str. 7,
35385 Giessen, Germany
Wagenlehner@aol.com

@Supplementary material
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Figures: N.H. Brockmeyer

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Cook RL, Hutchison SL, Ostergaard L, Braithwaite RS, Ness RB: Systematic review: noninvasive testing for Chlamydia trachomatis and Neisseria gonorrhoeae. Ann Intern Med 2005; 142: 914–25 CrossRef
22.
Yanofsky VR, Patel RV, Goldenberg G: Genital warts: a comprehensive review. J Clin Aesthet Dermatol 2012; 5: 25–36 MEDLINEPubMed Central
23.
Roth AM, Williams JA, Ly R, et al.: Changing sexually transmitted infection screening protocol will result in improved case finding for trichomonas vaginalis among high-risk female populations. Sex Transm Dis 2011; 38: 398–400 CrossRef MEDLINE
24.
Kreuter A, Brockmeyer NH, Hochdorfer B, et al.: Clinical spectrum and virologic characteristics of anal intraepithelial neoplasia in HIV infection. J Am Acad Dermatol 2005; 52: 603–8 CrossRef MEDLINE
25.
Robert Koch-Institut: HIV-Diagnosen und AIDS-Erkrankungen in Deutschland. Epidemiologisches Bulletin 2015; 27.
26.
Lohse N, Hansen AB, Pedersen G, et al.: Survival of persons with and without HIV infection in Denmark, 1995–2005. Ann Intern Med 2007; 146: 87–95 CrossRef MEDLINE
27.
May M, Gompels M, Delpech V, et al.: Impact of late diagnosis and treatment on life expectancy in people with HIV-1:
UK Collaborative HIV Cohort (UK CHIC) Study. BMJ 2011; 343: d6016 CrossRef MEDLINE PubMed Central
28.
Sabin CA: Do people with HIV infection have a normal life expectancy in the era of combination antiretroviral therapy? BMC Med 2013; 11: 251 CrossRef MEDLINE PubMed Central
29.
Smith CJ, Ryom L, Weber R, et al.: Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet 2014; 384: 241–8 CrossRef
30.
Weber R, Ruppik M, Rickenbach M, et al.: Decreasing mortality and changing patterns of causes of death in the Swiss HIV Cohort Study. HIV Med 2013; 14: 195–207 CrossRefMEDLINE
31.
Bernstein KT, Marcus JL, Nieri G, Philip SS, Klausner JD: Rectal gonorrhea and chlamydia reinfection is associated with increased risk of HIV seroconversion. J Acquir Immune Defic Syndr 2010; 53: 537–43 CrossRef MEDLINE
32.
Pathela P, Braunstein SL, Blank S, Schillinger JA: HIV incidence among men with and those without sexually transmitted rectal infections: estimates from matching against an HIV case registry. Clin Infect Dis 2013; 57: 1203–9 CrossRef MEDLINE
33.
Patel P, Bush T, Mayer K, et al.: Routine brief risk-reduction counseling with biannual STD testing reduces STD incidence among HIV-infected men who have sex with men in care. Sex Transm Dis 2012; 39: 470–4 CrossRef MEDLINE
34.
Robert Koch-Institut: Syphilis in Deutschland 2012. Epidemiologisches Bulletin 2013; 44.
35.
WHO: Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. 2015. apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf?ua=1 (last accessed on 10 December 2015).
36.
Cohen MS, Chen YQ, McCauley M, et al.: Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365: 493–505 CrossRef MEDLINE PubMed Central
37.
van de Laar TJ, Matthews GV, Prins M, Danta M: Acute hepatitis C in HIV-infected men who have sex with men: an emerging sexually transmitted infection. AIDS 2010; 24: 1799–812 CrossRef MEDLINE
38.
Cornberg M, Manns MP: New kids on the block—step by step to an ideal HCV therapy. Lancet 2015; 385: 1050–2 CrossRef
e1.
Kent CK, Chaw JK, Wong W, et al.: Prevalence of rectal, urethral, and pharyngeal chlamydia and gonorrhea detected in 2 clinical settings among men who have sex with men: San Francisco, California, 2003. Clin Infect Dis 2005; 41: 67–74 CrossRef MEDLINE
e2.
Keikawus A, Baumgarten A, Behrens G, et al.: Deutsch-Österreichische Leitlinien zur antiretroviralen Therapie der HIV-Infektion. In: AWMF, 2014. www.awmf.org/uploads/tx_szleitlinien/055–001l_Antiretrovirale_Therapie_der_HIV_Infektion__2014–05.pdf (last accessed on 10 December 2015).
e3.
Aberg JA, Gallant JE, Ghanem KG, et al.: Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the infectious diseases Society of America. Clin Infect Dis 2014; 58: e1–34.
e4.
Workowski K, Berman, S, et al.: Sexually transmitted diseases treatment guidelines 2010. In: Centers for Disease Control and Prevention. MMWR 2010; 59: 1–110.
e5.
Serwadda D, Gray RH, Sewankambo NK, et al.: Human immunodeficiency virus acquisition associated with genital ulcer disease and herpes simplex virus type 2 infection: a nested case-control study in Rakai, Uganda. J Infect Dis 2003; 188: 1492–7 CrossRef MEDLINE
e6.
Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ: Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 2006; 20: 73–83 CrossRef
e7.
Janata O, Reisinger E: Infektiologie. Aktuelle Aspekte 2001/2002. Wien: Springer Verlag 2001.
e8.
Deutsche STI-Gesellschaft: STI-Leitfaden 2014. www.dstig.de/literaturleitlinienlinks/sti-leitfaden.html (last accessed on 10
December 2015).
e9.
Li DK, Raebel MA, Cheetham TC, et al.: Genital herpes and its treatment in relation to preterm delivery. Am J Epidemiol 2014; 180: 1109–17 CrossRef MEDLINE
e10.
Bradshaw CS, Tabrizi SN, Read TR, et al.: Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure. J Infect Dis 2006; 193: 336–45 CrossRef MEDLINE
e11.
Anagrius C, Lore B, Jensen JS: Treatment of mycoplasma genitalium. Observations from a Swedish STD clinic. PLoS One 2013; 8: e61481 CrossRef MEDLINE PubMed Central
e12.
Marrazzo JM, Handsfield HH, Whittington WL: Predicting chlamydial and gonococcal cervical infection: implications for management of cervicitis. Obstet Gynecol 2002; 100: 579–84 CrossRef
e13.
Moodley D, Moodley P, Sebitloane M, et al.: High prevalence and incidence of asymptomatic sexually transmitted infections during pregnancy and postdelivery in KwaZulu Natal, South Africa. Sex Transm Dis 2015; 42: 43–7 CrossRef MEDLINE
e14.
Kissinger P, Adamski A: Trichomoniasis and HIV interactions:
a review. Sex Transm Infect 2013; 89: 426–33 CrossRef MEDLINE PubMed Central
e15.
Schwebke JR, Hobbs MM, Taylor SN, et al.: Molecular testing for trichomonas vaginalis in women: results from a prospective U.S. clinical trial. J Clin Microbiol 2011; 49: 4106–11 CrossRef MEDLINE PubMed Central
e16.
Ramqvist T, Grun N, Dalianis T: Human papillomavirus and tonsillar and base of tongue cancer. Viruses 2015; 7: 1332–43 CrossRef MEDLINEPubMed Central
e17.
Nielson CM, Harris RB, Dunne EF, et al.: Risk factors for anogenital human papillomavirus infection in men. J Infect Dis 2007; 196: 1137–45 CrossRef MEDLINE PubMed Central
e18.
Brockmeyer N, Degen O, Eldering G, et al.: Anale Dysplasien und Analkarzinome bei HIV-Infizierten: Prävention, Diagnostik, Therapie. In: AWMF; 2014.
e19.
Samji H, Cescon A, Hogg RS, et al.: Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PLoS One 2013; 8: e81355.
e20.
Hollingsworth TD, Anderson RM, Fraser C: HIV-1 transmission, by stage of infection. J Infect Dis 2008; 198: 687–93 CrossRef MEDLINE
e21.
Fiebig EW, Wright DJ, Rawal BD, et al.: Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS 2003; 17: 1871–9 CrossRef MEDLINE
e22.
Vernazza P, Hirschel, B, Bernasconi, E, Flepp, M: HIV-infizierte Menschen ohne andere STD sind unter wirksamer antiretroviraler Therapie sexuell nich infektiös. Schweizerische Ärztezeitung 2008; 89: 165–169.
e23.
Patel P, Borkowf CB, Brooks JT, Lasry A, Lansky A, Mermin J: Estimating per-act HIV transmission risk: a systematic review. AIDS 2014; 28: 1509–19 CrossRef MEDLINE
e24.
Rodger A, Bruun T, Weait M, et al.: HIV-transmission risk through condomless sex if the HIV positive partner on suppressiv ART: PARTNER Study. In: CROI. Boston; 2014.
e25.
Department of Health and Human Services: Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use of an-tiretroviral agents in HIV-1-infected adults and adolescents. www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. (last accessed on 10 December 2015)
e26.
Urbanus AT, van de Laar TJ, Stolte IG, et al.: Hepatitis C virus infections among HIV-infected men who have sex with men: an expanding epidemic. AIDS 2009; 23: F1–7.
e27.
European Association for Study of Liver: EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2014; 60: 392–420 CrossRef MEDLINE
e28.
Sarrazin C, Berg T, Buggisch P, et al.: Aktuelle Empfehlung zur Therapie der chronischen Hepatitis C Addendum vom 18. 2. 2015 zur S3-Leitlinie 021/012. www.awmf.org/fileadmin/user_upload/Leitlinien/021_D_Ges_fuer_Verdauungs-_und_Stoffwechselkrankheiten/021–012a_S3_Hepatitis-C-Addendum_2015–02.pdf (Last accessed on 10 December 2015).
e29.
Wedemeyer H. [Treatment of hepatitis C: what is known?]. Internist 2014; 55: 1419–26 CrossRef MEDLINE
Department of Urology, Pediatric Urology and Andrology, Medical Faculty of the Justus Liebig University Giessen: Prof. Dr. med. Wagenlehner
Department of Dermatology, Venerology and Allergology, St. Josef-Hospital of the Medical Faculty, Ruhr-University Bochum: Prof. Dr. med. Brockmeyer
Medizinische Klinik und Poliklinik II, Justus-Liebig-Universität, Giessen:
Dr. med. Discher
Department of Obstetrics and Gynecology of the Ludwig-Maximilians-Universität München: Prof. Dr. med. Friese
Institute for Medical Microbiology and Infection Control, Goethe University Frankfurt am Main: Prof. Dr. med. Wichelhaus
HIV testing
HIV testing
Box
HIV testing
Acute herpes simplex virus infection in the area of the mons pubis
Acute herpes simplex virus infection in the area of the mons pubis
Figure 1
Acute herpes simplex virus infection in the area of the mons pubis
Primary infection and secondary stage of syphilis: ulcus durum on the upper lip; maculopapular facial rash
Primary infection and secondary stage of syphilis: ulcus durum on the upper lip; maculopapular facial rash
Figure 2
Primary infection and secondary stage of syphilis: ulcus durum on the upper lip; maculopapular facial rash
Various appearances and localizations of condylomatous warts
Various appearances and localizations of condylomatous warts
Figure 3
Various appearances and localizations of condylomatous warts
Purulent urethral discharge in gonorrheal urethritis
Purulent urethral discharge in gonorrheal urethritis
Figure 4
Purulent urethral discharge in gonorrheal urethritis
The treatment of sexually transmitted diseases
The treatment of sexually transmitted diseases
Table
The treatment of sexually transmitted diseases
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14. Williams JR, Jordan JC, Davis EA, Garnett GP: Suppressive valacyclovir therapy: impact on the population spread of HSV-2 infection. Sex Transm Dis 2007; 34: 123–31 CrossRef MEDLINE
15. Bartelsman M, Straetemans M, Vaughan K, et al.: Comparison of two Gram stain point-of-care systems for urogenital gonorrhoea among high-risk patients: diagnostic accuracy and cost-effectiveness before and after changing the screening algorithm at an STI clinic in Amsterdam. Sex Transm Infect 2014; 90: 358–62 CrossRef MEDLINE
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19. Horn NN, Kresken M, Korber-Irrgang B, et al. Antimicrobial susceptibility and molecular epidemiology of Neisseria gonorrhoeae in Germany. Int J Med Microbiol 2014; 304: 586–91 CrossRef MEDLINE
20. Horner P, Blee K, Adams E: Time to manage mycoplasma genitalium as an STI: but not with azithromycin 1 g! Curr Opin Infect Dis 2014; 27: 68–74 CrossRef MEDLINE
21. Cook RL, Hutchison SL, Ostergaard L, Braithwaite RS, Ness RB: Systematic review: noninvasive testing for Chlamydia trachomatis and Neisseria gonorrhoeae. Ann Intern Med 2005; 142: 914–25 CrossRef
22.Yanofsky VR, Patel RV, Goldenberg G: Genital warts: a comprehensive review. J Clin Aesthet Dermatol 2012; 5: 25–36 MEDLINEPubMed Central
23.Roth AM, Williams JA, Ly R, et al.: Changing sexually transmitted infection screening protocol will result in improved case finding for trichomonas vaginalis among high-risk female populations. Sex Transm Dis 2011; 38: 398–400 CrossRef MEDLINE
24. Kreuter A, Brockmeyer NH, Hochdorfer B, et al.: Clinical spectrum and virologic characteristics of anal intraepithelial neoplasia in HIV infection. J Am Acad Dermatol 2005; 52: 603–8 CrossRef MEDLINE
25.Robert Koch-Institut: HIV-Diagnosen und AIDS-Erkrankungen in Deutschland. Epidemiologisches Bulletin 2015; 27.
26.Lohse N, Hansen AB, Pedersen G, et al.: Survival of persons with and without HIV infection in Denmark, 1995–2005. Ann Intern Med 2007; 146: 87–95 CrossRef MEDLINE
27.May M, Gompels M, Delpech V, et al.: Impact of late diagnosis and treatment on life expectancy in people with HIV-1:
UK Collaborative HIV Cohort (UK CHIC) Study. BMJ 2011; 343: d6016 CrossRef MEDLINE PubMed Central
28.Sabin CA: Do people with HIV infection have a normal life expectancy in the era of combination antiretroviral therapy? BMC Med 2013; 11: 251 CrossRef MEDLINE PubMed Central
29. Smith CJ, Ryom L, Weber R, et al.: Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet 2014; 384: 241–8 CrossRef
30. Weber R, Ruppik M, Rickenbach M, et al.: Decreasing mortality and changing patterns of causes of death in the Swiss HIV Cohort Study. HIV Med 2013; 14: 195–207 CrossRefMEDLINE
31. Bernstein KT, Marcus JL, Nieri G, Philip SS, Klausner JD: Rectal gonorrhea and chlamydia reinfection is associated with increased risk of HIV seroconversion. J Acquir Immune Defic Syndr 2010; 53: 537–43 CrossRef MEDLINE
32. Pathela P, Braunstein SL, Blank S, Schillinger JA: HIV incidence among men with and those without sexually transmitted rectal infections: estimates from matching against an HIV case registry. Clin Infect Dis 2013; 57: 1203–9 CrossRef MEDLINE
33. Patel P, Bush T, Mayer K, et al.: Routine brief risk-reduction counseling with biannual STD testing reduces STD incidence among HIV-infected men who have sex with men in care. Sex Transm Dis 2012; 39: 470–4 CrossRef MEDLINE
34.Robert Koch-Institut: Syphilis in Deutschland 2012. Epidemiologisches Bulletin 2013; 44.
35.WHO: Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. 2015. apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf?ua=1 (last accessed on 10 December 2015).
36. Cohen MS, Chen YQ, McCauley M, et al.: Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365: 493–505 CrossRef MEDLINE PubMed Central
37. van de Laar TJ, Matthews GV, Prins M, Danta M: Acute hepatitis C in HIV-infected men who have sex with men: an emerging sexually transmitted infection. AIDS 2010; 24: 1799–812 CrossRef MEDLINE
38. Cornberg M, Manns MP: New kids on the block—step by step to an ideal HCV therapy. Lancet 2015; 385: 1050–2 CrossRef
e1. Kent CK, Chaw JK, Wong W, et al.: Prevalence of rectal, urethral, and pharyngeal chlamydia and gonorrhea detected in 2 clinical settings among men who have sex with men: San Francisco, California, 2003. Clin Infect Dis 2005; 41: 67–74 CrossRef MEDLINE
e2.Keikawus A, Baumgarten A, Behrens G, et al.: Deutsch-Österreichische Leitlinien zur antiretroviralen Therapie der HIV-Infektion. In: AWMF, 2014. www.awmf.org/uploads/tx_szleitlinien/055–001l_Antiretrovirale_Therapie_der_HIV_Infektion__2014–05.pdf (last accessed on 10 December 2015).
e3. Aberg JA, Gallant JE, Ghanem KG, et al.: Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the infectious diseases Society of America. Clin Infect Dis 2014; 58: e1–34.
e4.Workowski K, Berman, S, et al.: Sexually transmitted diseases treatment guidelines 2010. In: Centers for Disease Control and Prevention. MMWR 2010; 59: 1–110.
e5.Serwadda D, Gray RH, Sewankambo NK, et al.: Human immunodeficiency virus acquisition associated with genital ulcer disease and herpes simplex virus type 2 infection: a nested case-control study in Rakai, Uganda. J Infect Dis 2003; 188: 1492–7 CrossRef MEDLINE
e6.Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ: Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 2006; 20: 73–83 CrossRef
e7.Janata O, Reisinger E: Infektiologie. Aktuelle Aspekte 2001/2002. Wien: Springer Verlag 2001.
e8.Deutsche STI-Gesellschaft: STI-Leitfaden 2014. www.dstig.de/literaturleitlinienlinks/sti-leitfaden.html (last accessed on 10
December 2015).
e9.Li DK, Raebel MA, Cheetham TC, et al.: Genital herpes and its treatment in relation to preterm delivery. Am J Epidemiol 2014; 180: 1109–17 CrossRef MEDLINE
e10.Bradshaw CS, Tabrizi SN, Read TR, et al.: Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure. J Infect Dis 2006; 193: 336–45 CrossRef MEDLINE
e11.Anagrius C, Lore B, Jensen JS: Treatment of mycoplasma genitalium. Observations from a Swedish STD clinic. PLoS One 2013; 8: e61481 CrossRef MEDLINE PubMed Central
e12.Marrazzo JM, Handsfield HH, Whittington WL: Predicting chlamydial and gonococcal cervical infection: implications for management of cervicitis. Obstet Gynecol 2002; 100: 579–84 CrossRef
e13.Moodley D, Moodley P, Sebitloane M, et al.: High prevalence and incidence of asymptomatic sexually transmitted infections during pregnancy and postdelivery in KwaZulu Natal, South Africa. Sex Transm Dis 2015; 42: 43–7 CrossRef MEDLINE
e14.Kissinger P, Adamski A: Trichomoniasis and HIV interactions:
a review. Sex Transm Infect 2013; 89: 426–33 CrossRef MEDLINE PubMed Central
e15.Schwebke JR, Hobbs MM, Taylor SN, et al.: Molecular testing for trichomonas vaginalis in women: results from a prospective U.S. clinical trial. J Clin Microbiol 2011; 49: 4106–11 CrossRef MEDLINE PubMed Central
e16.Ramqvist T, Grun N, Dalianis T: Human papillomavirus and tonsillar and base of tongue cancer. Viruses 2015; 7: 1332–43 CrossRef MEDLINEPubMed Central
e17.Nielson CM, Harris RB, Dunne EF, et al.: Risk factors for anogenital human papillomavirus infection in men. J Infect Dis 2007; 196: 1137–45 CrossRef MEDLINE PubMed Central
e18.Brockmeyer N, Degen O, Eldering G, et al.: Anale Dysplasien und Analkarzinome bei HIV-Infizierten: Prävention, Diagnostik, Therapie. In: AWMF; 2014.
e19.Samji H, Cescon A, Hogg RS, et al.: Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PLoS One 2013; 8: e81355.
e20.Hollingsworth TD, Anderson RM, Fraser C: HIV-1 transmission, by stage of infection. J Infect Dis 2008; 198: 687–93 CrossRef MEDLINE
e21.Fiebig EW, Wright DJ, Rawal BD, et al.: Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS 2003; 17: 1871–9 CrossRef MEDLINE
e22.Vernazza P, Hirschel, B, Bernasconi, E, Flepp, M: HIV-infizierte Menschen ohne andere STD sind unter wirksamer antiretroviraler Therapie sexuell nich infektiös. Schweizerische Ärztezeitung 2008; 89: 165–169.
e23.Patel P, Borkowf CB, Brooks JT, Lasry A, Lansky A, Mermin J: Estimating per-act HIV transmission risk: a systematic review. AIDS 2014; 28: 1509–19 CrossRef MEDLINE
e24.Rodger A, Bruun T, Weait M, et al.: HIV-transmission risk through condomless sex if the HIV positive partner on suppressiv ART: PARTNER Study. In: CROI. Boston; 2014.
e25.Department of Health and Human Services: Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use of an-tiretroviral agents in HIV-1-infected adults and adolescents. www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. (last accessed on 10 December 2015)
e26.Urbanus AT, van de Laar TJ, Stolte IG, et al.: Hepatitis C virus infections among HIV-infected men who have sex with men: an expanding epidemic. AIDS 2009; 23: F1–7.
e27.European Association for Study of Liver: EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2014; 60: 392–420 CrossRef MEDLINE
e28.Sarrazin C, Berg T, Buggisch P, et al.: Aktuelle Empfehlung zur Therapie der chronischen Hepatitis C Addendum vom 18. 2. 2015 zur S3-Leitlinie 021/012. www.awmf.org/fileadmin/user_upload/Leitlinien/021_D_Ges_fuer_Verdauungs-_und_Stoffwechselkrankheiten/021–012a_S3_Hepatitis-C-Addendum_2015–02.pdf (Last accessed on 10 December 2015).
e29. Wedemeyer H. [Treatment of hepatitis C: what is known?]. Internist 2014; 55: 1419–26 CrossRef MEDLINE