Development of New Antimicrobials for Urogenital Gonorrhea Therapy: Clinical Trial Design Considerations.

Gonorrhea remains a major public health challenge, and current recommendations for gonorrhea treatment are threatened by evolving antimicrobial resistance and a diminished pipeline for new antibiotics. Evaluations of potential new treatments for gonorrhea currently make limited use of new understanding of the pharmacokinetic and pharmacodynamic contributors to effective therapy, the prevention of antimicrobial resistance, and newer designs for clinical trials. They are hampered by the requirement to utilize combination ceftriaxone/azithromycin therapy as the comparator regimen in noninferiority trials designed to seek an indication for gonorrhea therapy. Evolving gonococcal epidemiology and clinical trial design constraints hinder the enrollment of those populations at the greatest risk for gonorrhea (adolescents, women, and persons infected with antibiotic-resistant Neisseria gonorrhoeae). This article summarizes a recent meeting on the evaluation process for antimicrobials for urogenital gonorrhea treatment and encourages the consideration of new designs for the evaluation of gonorrhea therapy.

Performance of a Dual Human Immunodeficiency Virus/Syphilis Rapid Test Compared With Conventional Serological Testing for Syphilis and Human Immunodeficiency Virus in a Laboratory Setting: Results From the Zimbabwe STI Etiology Study.

BACKGROUND: Dual human immunodeficiency virus (HIV)/syphilis rapid, point-of-care testing may enhance syphilis screening among high-risk populations, increase case finding, reduce time to treatment, and prevent complications. We assessed the laboratory-based performance of a rapid dual HIV/syphilis test using serum collected from patients enrolled in the Zimbabwe Sexually Transmitted Infections (STI) Etiology study. METHODS: Blood specimens were collected from patients presenting with STI syndromes in 6, predominantly urban STI clinics in different regions of Zimbabwe. All specimens were tested at a central research laboratory using the Standard Diagnostics Bioline HIV/Syphilis Duo test. The treponemal syphilis component of the dual rapid test was compared with the Treponema pallidum hemagglutination assay (TPHA) as a gold standard comparator, both alone or in combination with a nontreponemal test, the rapid plasma reagin test. The HIV component of the dual test was compared with a combination of HIV rapid tests conducted at the research laboratory following the Zimbabwe national HIV testing algorithm. RESULTS: Of 600 men and women enrolled in the study, 436 consented to serological syphilis and HIV testing and had specimens successfully tested by all assays. The treponemal component of the dual test had a sensitivity of 66.2% (95% confidence interval [CI], 55.2%-77.2%) and a specificity of 96.4% (95% CI, 94.5%-98.3%) when compared with TPHA; the sensitivity increased to 91.7% (95% CI, 82.6%-99.9%) when both TPHA and rapid plasma reagin were positive. The HIV component of the dual test had a sensitivity of 99.4% (95% CI, 98.4%-99.9%) and a specificity of 100% (95% CI, 99.9%-100%) when compared with the HIV testing algorithm. CONCLUSIONS: Laboratory performance of the SD Bioline HIV/Syphilis Duo test was high for the HIV component of the test. Sensitivity of the treponemal component was lower than reported from most laboratory-based evaluations in the literature. However, sensitivity of the test increased substantially among patients more likely to have active syphilis for which results of both standard treponemal and nontreponemal tests were positive.

Serological Markers for Syphilis Among Persons Presenting With Syndromes Associated With Sexually Transmitted Infections: Results From the Zimbabwe STI Etiology Study.

BACKGROUND: Syphilis prevalence in sub-Saharan Africa appears to be stable or declining but is still the highest globally. Ongoing sentinel surveillance in high-risk populations is necessary to inform management and detect changes in syphilis trends. We assessed serological syphilis markers among persons with sexually transmitted infections in Zimbabwe. METHODS: We studied a predominantly urban, regionally diverse group of women and men presenting with genital ulcer disease (GUD), women with vaginal discharge and men with urethral discharge at clinics in Zimbabwe. Syphilis tests included rapid plasma reagin and the Treponema pallidum hemagglutination assay. RESULTS: Among 436 evaluable study participants, 36 (8.3%) tested positive for both rapid plasma reagin and Treponema pallidum hemagglutination assay: women with GUD: 19.2%, men with GUD: 12.6%, women with vaginal discharge: 5.7% and men with urethral discharge: 1.5% (P < 0.0001). CONCLUSIONS: Syphilis rates in Zimbabwe are high in sentinel populations, especially men and women with GUD.

HIV infection in patients with sexually transmitted infections in Zimbabwe - Results from the Zimbabwe STI etiology study.

BACKGROUND: HIV and other sexually transmitted infections (STI) frequently co-occur. We conducted HIV diagnostic testing in an assessment of the etiologies of major STI syndromes in Zimbabwe. METHODS: A total of 600 patients were enrolled at six geographically diverse, high-volume STI clinics in Zimbabwe in 2014-15: 200 men with urethral discharge, 200 women with vaginal discharge, and 100 men and 100 women each with genital ulcer disease (GUD). Patients completed a questionnaire, underwent a genital examination, and had specimens taken for etiologic testing. Patients were offered, but not required to accept, HIV testing using a standard HIV algorithm in which two rapid tests defined a positive result. RESULTS: A total of 489 participants (81.5%) accepted HIV testing; 201 (41.1%) tested HIV-1-positive, including 16 (11.9%) of 134 participants who reported an HIV-negative status at study enrollment, and 58 (28.2%) of 206 participants who reported their HIV status as unknown. Of 147 who self-reported being HIV-positive at study enrollment, 21 (14.3%) tested HIV negative. HIV infection prevalence was higher in women (47.3%) than in men (34.8%, p<0.01), and was 28.5% in men with urethral discharge, 40.5% in women with vaginal discharge, 45.2% in men with GUD, and 59.8% in women with GUD (p<0.001). CONCLUSIONS: The high prevalence of HIV infection in STI clinic patients in Zimbabwe underscores the importance of providing HIV testing and referral for indicated prevention and treatment services for this population. The discrepancy between positive self-reported and negative study HIV test results highlights the need for operator training, strict attention to laboratory quality assurance, and clear communication with patients about their HIV infection status.

The Etiology of Vaginal Discharge Syndrome in Zimbabwe: Results from the Zimbabwe STI Etiology Study.

INTRODUCTION: Symptomatic vaginal discharge is a common gynecological condition managed syndromically in most developing countries. In Zimbabwe, women presenting with symptomatic vaginal discharge are treated with empirical regimens that commonly cover both sexually transmitted infections (STIs) and reproductive tract infections, typically including a combination of an intramuscular injection of kanamycin, and oral doxycycline and metronidazole regimens. This study was conducted to determine the current etiology of symptomatic vaginal discharge and assess adequacy of current syndromic management guidelines. METHODS: We enrolled 200 women with symptomatic vaginal discharge presenting at 6 STI clinics in Zimbabwe. Microscopy was used to detect bacterial vaginosis and yeast infection. Nucleic acid amplifications tests were used to detect Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, and Mycoplasma genitalium. In addition, serologic testing was performed to detect human immunodeficiency virus (HIV) infection. RESULTS: Of the 200 women, 146 (73%) had an etiology detected, including bacterial vaginosis (24.7%); N. gonorrhoeae (24.0%); yeast infection (20.7%); T. vaginalis (19.0%); C. trachomatis (14.0%) and M. genitalium (7.0%). Among women with STIs (N = 90), 62 (68.9%) had a single infection, 18 (20.0%) had a dual infection, and 10 (11.1%) had 3 infections.Of 158 women who consented to HIV testing, 64 (40.5%) were HIV infected.The syndromic management regimen covered 115 (57.5%) of the women in the sample who had gonorrhea, chlamydia, M. genitalium, or bacterial vaginosis, whereas 85 (42.5%) of women were treated without such diagnosis. CONCLUSIONS: Among women presenting with symptomatic vaginal discharge, bacterial vaginosis was the most common etiology, and gonorrhea was the most frequently detected STI. The current syndromic management algorithm is suboptimal for coverage of women presenting with symptomatic vaginal discharge; addition of point of care testing could compliment the effectiveness of the syndromic approach.

The Etiology of Male Urethral Discharge in Zimbabwe: Results from the Zimbabwe STI Etiology Study.

INTRODUCTION: Sexually transmitted infections (STIs) are managed syndromically in most developing countries. In Zimbabwe, men presenting with urethral discharge are treated with a single intramuscular dose of kanamycin or ceftriaxone in combination with a week's course of oral doxycycline. This study was designed to assess the current etiology of urethral discharge and other STIs to inform current syndromic management regimens. METHODS: We conducted a study among 200 men with urethral discharge presenting at 6 regionally diverse STI clinics in Zimbabwe. Urethral specimens were tested by multiplex polymerase chain reaction testing for Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, and Trichomonas vaginalis. In addition, serologic testing for syphilis and HIV was performed. RESULTS: Among the 200 studied men, one or more pathogens were identified in 163 (81.5%) men, including N. gonorrhoeae in 147 (73.5%), C. trachomatis in 45 (22.5%), T. vaginalis in 8 (4.0%), and M. genitalium in 7 (3.5%). Among all men, 121 (60%) had a single infection, 40 (20%) had dual infections, and 2 (1%) had 3 infections. Among the 45 men with C. trachomatis, 36 (80%) were coinfected with N. gonorrhoeae. Overall, 156 (78%) men had either N. gonorrhoeae or C. trachomatis identified. Of 151 men who consented to HIV testing, 43 (28.5%) tested positive. There were no differences in HIV status by study site or by urethral pathogen detected. CONCLUSIONS: Among men presenting at Zimbabwe STI clinics with urethral discharge, N. gonorrhoeae and C. trachomatis are the most commonly associated pathogens. Current syndromic management guidelines seem to be adequate for the treatment for symptomatic men, but future guidelines must be informed by ongoing monitoring of gonococcal resistance.

The Etiology of Genital Ulcer Disease and Coinfections With Chlamydia trachomatis and Neisseria gonorrhoeae in Zimbabwe: Results From the Zimbabwe STI Etiology Study.

BACKGROUND: In many countries, sexually transmitted infections (STIs) are treated syndromically. Thus, patients diagnosed as having genital ulcer disease (GUD) in Zimbabwe receive a combination of antimicrobials to treat syphilis, chancroid, lymphogranuloma venereum (LGV), and genital herpes. Periodic studies are necessary to assess the current etiology of GUD and assure the appropriateness of current treatment guidelines. MATERIALS AND METHODS: We selected 6 geographically diverse clinics in Zimbabwe serving high numbers of STI cases to enroll men and women with STI syndromes, including GUD. Sexually transmitted infection history and risk behavioral data were collected by questionnaire and uploaded to a Web-based database. Ulcer specimens were obtained for testing using a validated multiplex polymerase chain reaction (M-PCR) assay for Treponema pallidum (TP; primary syphilis), Haemophilus ducreyi (chancroid), LGV-associated strains of Chlamydia trachomatis, and herpes simplex virus (HSV) types 1 and 2. Blood samples were collected for testing with HIV, treponemal, and nontreponemal serologic assays. RESULTS: Among 200 GUD patients, 77 (38.5%) were positive for HSV, 32 (16%) were positive for TP, and 2 (1%) were positive for LGV-associated strains of C trachomatis. No H ducreyi infections were detected. No organism was found in 98 (49.5%) of participants. The overall HIV positivity rate was 52.2% for all GUD patients, with higher rates among women compared with men (59.8% vs 45.2%, P < 0.05) and among patients with HSV (68.6% vs 41.8%, P < 0.0001). Among patients with GUD, 54 (27.3%) had gonorrhea and/or chlamydia infection. However, in this latter group, 66.7% of women and 70.0% of men did not have abnormal vaginal or urethral discharge on examination. CONCLUSIONS: Herpes simplex virus is the most common cause of GUD in our survey, followed by T. pallidum. No cases of chancroid were detected. The association of HIV infections with HSV suggests high risk for cotransmission; however, some HSV ulcerations may be due to HSV reactivation among immunocompromised patients. The overall prevalence of gonorrhea and chlamydia was high among patients with GUD and most of them did not meet the criteria for concomitant syndromic management covering these infections.

A historical note on the association between the legal status of expedited partner therapy and physician practice.

Potential legal liability for practicing expedited partner therapy is a common concern among providers, although it has been uncertain how these concerns translate into clinical practice. This study suggests that providers are more likely to practice expedited partner therapy in more favorable legal environments.