Anne Rompalo

A Randomized Trial of Enhanced Therapy for Early Syphilis in Patients with and without Human Immunodeficiency Virus Infection

BACKGROUND Reports of neurosyphilis and invasion of cerebrospinal fluid by Treponema pallidum in patients with human immunodeficiency virus (HIV) infection have led to doubts about the adequacy of the recommended penicillin G benzathine therapy for early syphilis. METHODS In a multicenter, randomized, double-blind trial, we assessed two treatments for early syphilis: 2.4 million units of penicillin G benzathine and that therapy enhanced with a 10-day course of amoxicillin and probenecid. The serologic and clinical responses of patients with and without HIV infection were studied during one year of follow-up. RESULTS From 1991 through 1994, 541 patients were enrolled, including 101 patients (19 percent) who had HIV infection but differed little from the uninfected patients in their clinical presentations. The rates at which chancres and rashes resolved did not differ significantly according to treatment assignment or HIV status. Serologically defined treatment failures were more common among the HIV-infected patients. The single clinically defined treatment failure was in an HIV-infected patient. Rates of serologically defined treatment failure did not differ according to treatment group (18 percent at six months with usual therapy; 17 percent with enhanced therapy). T. pallidum was found at enrollment in the cerebrospinal fluid of 32 of 131 patients (24 percent) and after therapy in 7 of 35 patients tested. None had clinically evident neurosyphilis, and the rate of detection of T. pallidum did not differ according to HIV status. CONCLUSIONS After treatment for primary or secondary syphilis, the HIV-infected patients responded less well serologically than the patients without HIV infection, but clinically defined failure was uncommon in both groups. Enhanced treatment with amoxicillin and probenecid did not improve the outcomes. Although T. pallidum was detected in cerebrospinal fluid before therapy in a quarter of the patients tested, such a finding did not predict treatment failure. The current recommendations for treating early syphilis appear adequate for most patients, whether or not they have HIV infection.

Condom use to prevent incident STDs: the validity of self-reported condom use.

Background Studies of sexual behavior and of interventions designed to reduce human immunodeficiency virus risk usually depend on self-report. Validation of self-reported condom use measures has not been previously reported in an urban population at high risk for sexually transmitted diseases and human immunodeficiency virus. Methods A prospective cohort study was performed in subjects recruited from sexually transmitted disease clinics in Baltimore. At enrollment, a questionnaire was administered that assessed human immunodeficiency virus risk factors and sexually transmitted disease history, and used a retrospective calendar to assess sexual events and condom use over the previous 30 days. Clinical evaluation was performed for sexually transmitted diseases. At follow-up 3 months later, the same procedures were repeated. Incident sexually transmitted diseases at follow-up were defined as new culture or serologically documented diagnoses of gonorrhea, chlamydia, syphilis, or trichomoniasis. Results In the 323 male and 275 female (total = 598) subjects who completed a follow-up visit, 21% reported using condoms for every act of sexual intercourse over the previous 30 days, 21% reported occasionally using condoms, and 59% reported not using condoms. At follow-up, 21% of subjects had new incident gonorrhea, chlamydia, syphilis, or trichomoniasis. Fifteen percent of the men who were “always” condom users had incident sexually transmitted diseases compared with 15.3% of “never users;” 23.5% of women who were “always” users had incident sexually transmitted diseases compared with 26.8% of “never” users. Conclusions In this high-risk population, self-reported condom use is not associated with lower sexually transmitted disease incidence. This finding suggests that self-reported condom use measures, even in a research setting, may be subject to substantial reporting bias.

Cerebrospinal Fluid Abnormalities in Patients with Syphilis: Association with Clinical and Laboratory Features

OBJECTIVE To define clinical and laboratory features that identify patients with neurosyphilis. METHODS Subjects (n=326) with syphilis but no previous neurosyphilis who met 1993 Centers for Disease Control and Prevention criteria for lumbar puncture underwent standardized history, neurological examination, venipuncture, and lumbar puncture. Neurosyphilis was defined as a cerebrospinal fluid (CSF) white blood cell count >20 cells/ microL or reactive CSF Venereal Disease Research Laboratory (VDRL) test result. RESULTS Sixty-five subjects (20.1%) had neurosyphilis. Early syphilis increased the odds of neurosyphilis in univariate but not multivariate analyses. In multivariate analyses, serum rapid plasma reagin (RPR) titer > or =1 : 32 increased the odds of neurosyphilis 10.85-fold in human immunodeficiency virus (HIV)-uninfected subjects and 5.98-fold in HIV-infected subjects. A peripheral blood CD4+ T cell count < or =350 cells/ microL conferred 3.10-fold increased odds of neurosyphilis in HIV-infected subjects. Similar results were obtained when neurosyphilis was more stringently defined as a reactive CSF VDRL test result. CONCLUSION Serum RPR titer helps predict the likelihood of neurosyphilis. HIV-induced immune impairment may increase the risk of neurosyphilis.

Clinical manifestations of early syphilis by HIV status and gender: results of the syphilis and HIV study.

Background Despite reports of unusual clinical presentations and therapeutic responses among HIV-infected patients with syphilis, syphilis has not been regarded as a serious opportunistic infection that predictably progresses among most HIV-coinfected patients. Goal To define and describe differences in the presentation and response to treatment of early syphilis among HIV-infected and HIV-uninfected patients, to describe any differences by gender, and to determine if clinical presentation of central nervous system involvement predicted serologic failure. Design A prospective, multicenter, randomized, controlled trial of enhanced versus standard therapy to compare the benefit of enhanced therapy, the clinical importance of central nervous system involvement, and the clinical manifestations of early syphilis infection among HIV-infected and HIV-uninfected patients. Results The median number of ulcers was significantly greater among HIV-infected and HIV-uninfected patients, as was the percent of HIV-infected patients with multiple ulcers. Among patients diagnosed with secondary syphilis, a higher percentage of HIV-infected patients presented with genital ulcers [13/53 (25%)] than did HIV-uninfected patients [27/200 (14%)]. No differences between HIV-infected and HIV-uninfected patients were detected for other secondary syphilis manifestations. Although women presented more frequently with secondary syphilis than did men, no other gender differences in clinical manifestations were noted. Neurologic complaints were reported most frequently among patients with secondary syphilis [103/248 patients (42%)] compared with patients with primary syphilis [32/136 (24%)] and early latent syphilis [48/142, (34%)] (P < 0.05), but no differences in neurologic complaints were apparent by HIV status or CSF abnormalities. No neurologic complaints were significantly associated with serologic treatment failures at 6 months. Conclusions Overall, HIV infection had a small effect on the clinical manifestations of primary and secondary syphilis. Compared with HIV-uninfected patients, HIV-infected patients with primary syphilis tended to present more frequently with multiple ulcers, and HIV-infected patients with secondary syphilis presented with concomitant genitals ulcers more frequently.

Re-Evaluating the Treatment of Nongonococcal Urethritis: Emphasizing Emerging Pathogens–A Randomized Clinical Trial

BACKGROUND Nongonococcal urethritis (NGU) is a common chlamydia-associated syndrome in men; however, Trichomonas vaginalis and Mycoplasma genitalium are associated with its etiology and should be considered in approaches to therapy. We sought to determine whether the addition of tinidazole, an anti-trichomonal agent, to the treatment regimen would result in higher cure rates than those achieved with treatment with doxycycline or azithromycin alone. A secondary aim was to compare the efficacy of doxycycline therapy and with that of azithromycin therapy. METHODS Randomized, controlled, double-blinded phase IIB trial of men with NGU. Participants were randomized to receive doxycycline plus or minus tinidazole or azithromycin plus or minus tinidazole and were observed for up to 45 days. RESULTS The prevalences of Chlamydia trachomatis, M. genitalium, and T. vaginalis were 43%, 31%, and 13%, respectively. No pathogens were identified in 29% of participants. Clinical cure rates at the first follow-up visit were 74.5% (111 of 149 patients) for doxycycline-containing regimens and 68.6% (107 of 156 patients) for azithromycin-containing regimens. By the final visit, cure rates were 49% (73 of 149 patients) for doxycycline-containing regimens and 43.6% (68 of 156 patients) for azithromycin-containing regimens. There were no significant differences in clinical response rates among the treatment arms. However, the chlamydia clearance rate was 94.8% (55 of 58 patients) for the doxycycline arm and 77.4% (41 of 53 patients) for the azithromycin arm (P = .011), and the M. genitalium clearance rate was 30.8% (12 of 39 patients) for the doxycycline arm and 66.7% (30 of 45 patients) for the azithromycin arm (P = .002). CONCLUSIONS Addition of tinidazole to the treatment regimen did not result in higher cure rates but effectively eradicated trichomonas. Clinical cure rates were not significantly different between patients treated with doxycycline and those treated with azithromycin; however, doxycycline had significantly better efficacy against Chlamydia, whereas azithromycin was superior to doxycycline for the treatment of M. genitalium.

Development of proteinuria or elevated serum creatinine and mortality in HIV-infected women.

BackgroundData on the incidence and prognostic significance of renal dysfunction in HIV disease are limited. ObjectiveTo determine the incidence of proteinuria and elevated serum creatinine in HIV-positive and HIV-negative women and to determine whether these abnormalities are predictors of mortality or associated with causes of death listed on the death certificate in HIV-positive women. DesignThe incidence of proteinuria or elevated serum creatinine and mortality was assessed in a cohort of 885 HIV-positive women and 425 at-risk HIV-negative women. SettingWomen from the general community or HIV care clinics in four urban locations in the United States. Outcome MeasuresCreatinine of ≥1.4 mg/dL, proteinuria 2+ or more, or both. Deaths confirmed by a death certificate (92%) or medical record/community report (8%). ResultsAt baseline, 64 (7.2%) HIV-positive women and 10 (2.4%) HIV-negative women had proteinuria or elevated creatinine. An additional 128 (14%) HIV-positive women and 18 (4%) HIV-negative women developed these abnormalities over the next (mean) 21 months. Relative hazards of mortality were significantly increased (adjusted relative hazard = 2.5; 95% confidence interval: 1.9–3.3), and there were more renal causes recorded on death certificates (24/92 (26%) vs. 3/127 (2.7%), p < .0001) in HIV-infected women with, compared with those without these renal abnormalities. ConclusionsProteinuria, elevated serum creatinine, or both frequently occurred in these HIV-infected women. These renal abnormalities in HIV-infected women are associated with an increased risk of death after controlling for other risk factors and with an increased likelihood of having renal causes listed on the death certificate. The recognition and management of proteinuria and elevated serum creatinine should be a priority for HIV-infected persons.

Neurosyphilis in a clinical cohort of HIV-1-infected patients

Objectives:To describe the risk factors, clinical presentation, and long-term follow up of patients enrolled in a clinical cohort of HIV-infected patients who were diagnosed and treated for neurosyphilis. Methods:Comprehensive demographic, clinical, and therapeutic data were collected prospectively on all patients between 1990 and 2006. Patients were diagnosed with neurosyphilis if they had positive syphilis serologies and any of the following: (a) one or more cerebrospinal fluid abnormalities on lumbar puncture [white blood cells >10/μl; protein >50 mg/dl; reactive venereal diseases research laboratory], (b) an otherwise unexplained neurological finding. Results:Of 231 newly diagnosed syphilis cases, 41 neurosyphilis cases met entry criteria (median age 38.6 years, 79.1% male). Risk factors for neurosyphilis included a CD4 cell count of less than 350 cells/ml at the time of syphilis diagnosis (odds ratio: 2.87; 95% confidence interval: 1.18–7.02), a rapid plasma regain titer >1: 128 (2.83; 1.11–7.26), and male sex (2.46; 1.06–5.70). Use of any highly active antiretroviral therapy before syphilis infection reduced the odds of neurosyphilis by 65% (0.35; 0.14–0.91). Sixty-three percent of cases presented with early neurosyphilis and the median time to neurosyphilis diagnosis was 9 months. Symptomatic patients had more cerebrospinal fluid abnormalities on initial lumbar puncture than asymptomatic patients (P = 0.01). Follow-up lumbar puncture within 12 months revealed that only 38% had resolution of all cerebrospinal fluid abnormalities. At 1 year, 38% had persistence of their major symptom despite adequate treatment for neurosyphilis. Twelve of 41 (29%) patients were retreated for syphilis. Conclusion:Early neurosyphilis was common in this cohort. Highly active antiretroviral therapy to reverse immunosuppression may help mitigate neurological complications of syphilis.

Trichomonas vaginalis Polymerase Chain Reaction Compared with Standard Diagnostic and Therapeutic Protocols for Detection and Treatment of Vaginal Trichomoniasis

Wet preparation has limited sensitivity for diagnosis of Trichomonas vaginalis (TV) infection. An observational study of 337 women was conducted to evaluate a new polymerase chain reaction (PCR) test for TV. The sensitivities of wet preparation and TV culture were 52% (95% confidence interval [CI], 41-62) and 78% (95% CI, 69-86), respectively. TV PCR had a sensitivity of 84% (95% CI, 75-90) and a specificity of 94% (95% CI, 90-97). Metronidazole was provided to 67 (69%) of 97 women with TV because of TV on wet preparation, exposure to TV, or a diagnosis of bacterial vaginosis or pelvic inflammatory disease; however, if TV PCR had been used for diagnosis, 81 (84%) of 97 women with TV would have been treated (P=.02). TV is significantly undertreated using standard algorithms for metronidazole therapy. Given the association of trichomoniasis with perinatal morbidity and HIV transmission, women in high-risk groups may benefit from TV PCR.

The etiology of genital ulcer disease by multiplex polymerase chain reaction and relationship to HIV infection among patients attending sexually transmitted disease clinics in Pune, India

OBJECTIVES To determine the etiology of genital ulcer disease (GUD) among patients attending sexually transmitted disease (STD) clinics in Pune, India, and to examine the relationship to HIV infection and compare the clinical diagnosis of GUD with the results of a multiplex polymerase chain reaction (M-PCR) assay for Treponema pallidum, herpes simplex virus (HSV), and Hemophilus ducreyi infection. METHODS Between June 20, 1994, and September 26, 1994, 302 patients with a genital ulcer were evaluated. Clinical etiology of GUD was based on physical appearance and microbiologic evaluations which included darkfield microscopy and serology for syphilis. Swabs of each genital ulcer were tested for HSV antigen by enzyme immunoassay (Herpchek; Dupont, Wilmington, DE) and processed in a multiplex PCR assay (M-PCR; Roche, Branchburg, NJ) for simultaneous detection of HSV, Treponema pallidum, and Hemophilus ducreyi. RESULTS Two hundred seventy-seven men and 25 women with a median age of 25 were evaluated. The seroprevalence of HIV was 22.2%. The etiology of GUD as determined by M-PCR was HSV (26%), H. ducreyi (23%), T. pallidum (10%), and multiple infections (7%); no etiology was identified in 34%. HIV seroprevalence was higher among those patients positive for HSV compared with other etiologies (OR = 2.1, CI: 1.2-3.7; p = 0.01). When compared with M-PCR, the Herpchek test was 68.5% sensitive and 99.5% specific. Darkfield detection for T. pallidum was 39% sensitive and 82% specific, in contrast to rapid plasma reagin and fluorescent treponemal antibody absorption test, which was 66% sensitive and 90% specific. Clinical diagnosis alone or in combination with basic laboratory tests showed poor agreement with M-PCR.

Bacterial Pneumonia, HIV Therapy, and Disease Progression among HIV-Infected Women in the HIV Epidemiologic Research (HER) Study

BACKGROUND To determine the rate and predictors of community-acquired bacterial pneumonia and its effect on human immunodeficiency virus (HIV) disease progression in HIV-infected women, we performed a multiple-site, prospective study of HIV-infected women in 4 cities in the United States. METHODS During the period of 1993-2000, we observed 885 HIV-infected and 425 HIV-uninfected women with a history of injection drug use or high-risk sexual behavior. Participants underwent semiannual interviews, and CD4+ lymphocyte count and viral load were assessed in HIV-infected subjects. Data regarding episodes of bacterial pneumonia were ascertained from medical record reviews. RESULTS The rate of bacterial pneumonia among 885 HIV-infected women was 8.5 cases per 100 person-years, compared with 0.7 cases per 100 person-years in 425 HIV-uninfected women (P < .001). In analyses limited to follow-up after 1 January 1996, highly active antiretroviral therapy (HAART) and trimethoprim-sulfamethoxazole (TMP-SMX) use were associated with a decreased risk of bacterial pneumonia. Among women who had used TMP-SMX for 12 months, each month of HAART decreased bacterial pneumonia risk by 8% (adjusted hazard ratio [HR(adj)], 0.92; 95% confidence interval [CI], 0.89-0.95). Increments of 50 CD4+ cells/mm3 decreased the risk (HR(adj), 0.88; 95% CI, 0.84-0.93), and smoking doubled the risk (HR(adj), 2.12; 95% CI, 1.26-3.55). Bacterial pneumonia increased mortality risk (HR(adj), 5.02; 95% CI, 2.12-11.87), with adjustment for CD4+ lymphocyte count and duration of HAART and TMP-SMX use. CONCLUSIONS High rates of bacterial pneumonia persist among HIV-infected women. Although HAART and TMP-SMX treatment decreased the risk, bacterial pneumonia was associated with an accelerated progression to death. Interventions that improve HAART utilization and promote smoking cessation among HIV-infected women are warranted.