John M. Douglas

Treatment of genital warts with an immune-response modifier (imiquimod)

BACKGROUND Genital warts are a common sexually transmitted disease caused by human papillomavirus. Imiquimod is a novel immune-response modifier capable of inducing a variety of cytokines, including interferon alfa, tumor necrosis factor-alpha, as well as interleukins 1, 6, and 8. In animal models imiquimod has demonstrated antiviral, antitumor, and adjuvant activity. In vitro, imiquimod has no antiviral or antitumor activity. OBJECTIVE Our purpose was to determine the safety and efficacy of topical imiquimod for the treatment of external genital warts. METHODS This prospective double-blind, placebo-controlled, parallel design clinical trial was performed in three outpatient centers, a public health clinic, a university-based clinic, and a private practice. One hundred eight patients with external genital warts (predominantly white men) were entered into the trial. Fifty-one patients were randomly selected to receive 5% imiquimod cream; 57 patients were randomly chosen to receive placebo cream. Study medication was applied three times weekly for up to 8 weeks. Patients whose warts cleared completely were observed for up to 10 weeks to determine recurrence rates. RESULTS In the intent-to-treat analysis, the warts of 37% (19 of 51) of the imiquimod-treated patients and 0% (0 of 57) of the placebo group cleared completely (p < 0.001). In addition, many patients experienced a partial response. A reduction in baseline wart area of 80% or more was observed in 62% of imiquimod-treated patients (28 of 45) and 4% of the placebo group (2 of 50) (p < 0.001); a 50% reduction or more in wart area was noted in 76% of imiquimod-treated patients (34 of 45) and 8% of placebo recipients (4 of 50) (p < 0.001). Of imiquimod-treated patients whose warts cleared completely and who finished the 10-week follow-up period, 19% (3 of 16) experienced recurrences of warts. Imiquimod-treated patients experienced a significantly greater number of local inflammatory reactions than the placebo group. Symptoms and signs associated with the local inflammatory reactions included itching (54.2%), erythema (33.3%), burning (31.3%), irritation (16.7%), tenderness (12.5%), ulceration (10.4%), erosion (10.4%), and pain (8.3%). There were no differences in systemic reactions or laboratory abnormalities between treatment groups. CONCLUSION Topical 5% imiquimod cream appears to have a significant therapeutic effect in the treatment of external genital warts.

The Epidemiology of Antiretroviral Drug Resistance among Drug-Naive HIV-1-Infected Persons in 10 US Cities

BACKGROUND The prevalence and characteristics of persons with newly diagnosed human immunodeficiency virus (HIV) infections with or without evidence of mutations associated with drug resistance have not been well described. METHODS Drug-naive persons in whom HIV had been diagnosed during the previous 12 months and who did not have acquired immune deficiency syndrome were sequentially enrolled from 39 clinics and testing sites in 10 US cities during 1997-2001. Genotyping was conducted from HIV-amplification products, by automated sequencing. For specimens identified as having mutations previously associated with reduced antiretroviral-drug susceptibility, phenotypic testing was performed. RESULTS Of 1311 eligible participants, 1082 (83%) were enrolled and successfully tested; 8.3% had reverse transcriptase or major protease mutations associated with reduced antiretroviral-drug susceptibility. The prevalence of these mutations was 11.6% among men who had sex with men but was only 6.1% and 4.7% among women and heterosexual men, respectively. The prevalence was 5.4% and 7.9% among African American and Hispanic participants, respectively, and was 13.0% among whites. Among persons whose sexual partners reportedly took antiretroviral medications, the prevalence was 15.2%. CONCLUSIONS Depending on the characteristics of the patients tested, HIV-genotype testing prior to the initiation of therapy would identify a substantial number of infected persons with mutations associated with reduced antiretroviral-drug susceptibility.

External genital warts: diagnosis, treatment, and prevention.

External genital warts (EGWs) are visible warts that occur in the perigenital and perianal regions. They are due primarily to non-oncogenic human papillomavirus (HPV) types, usually types 6 and 11. Physical examination assisted by bright light and magnification is the recommended approach for primary diagnosis. Biopsy is indicated when EGWs are fixed to underlying structures or discolored or when standard therapies are not effective. Recurrences are common, and there is no single treatment that is superior to others. Among women with atypical squamous cells, molecular HPV testing may be useful in determining who should be referred for colposcopy. Condoms may provide some protection against HPV-related diseases and thus are recommended in new sexual relationships and when partnerships are not mutually monogamous. Because the efficacy of cesarean section in preventing vertical transmission of HPV infection from women with EGWs to their progeny has not been proved, it is not recommended.

Does measured behavior reflect STD risk ? : An analysis of Data from a randomized controlled Behavioral intervention study

Background: Many studies measure sex behavior to determine the efficacy of sexually transmitted disease (STD)/HIV prevention interventions. Goal: To determine how well measured behavior reflects STD incidence. Study Design: Data from a trial (Project RESPECT) were analyzed to compare behavior and incidence of STD (gonorrhea, chlamydia, syphilis, HIV) during two 6‐month intervals. Results: A total of 2879 persons had 5062 six‐monthly STD exams and interviews; 8.9% had a new STD in 6 months. Incidence was associated with demographic factors but only slightly associated with number of partners and number of unprotected sex acts with occasional partners. Many behaviors had paradoxical associations with STD incidence. After combining behavior variables to compare persons with highest and lowest risk behaviors, the STD incidence ratio was only 1.7. Conclusion: Behavioral interventions have prevented STD. We found people tend to have safe sex with risky partners and risky sex with safe partners. Therefore, it is difficult to extrapolate the disease prevention efficacy of an intervention from a measured effect on behavior alone.

Emerging Antimicrobial Resistance in Neisseria gonorrhoeae: Urgent Need to Strengthen Prevention Strategies

Neisseria gonorrhoeae infection can cause cervicitis, urethritis, proctitis, pelvic inflammatory disease with long-term sequelae (infertility, ectopic pregnancy, chronic pelvic pain), adverse outcomes of pregnancy, and increased susceptibility to and transmission of HIV infection (1, 2). Neisseria gonorrhoeae infection is the second most common notifiable disease in the United States, with 358366 cases reported in 2006 (3). However, reported cases probably represent an underestimate of the actual disease burden because of underdiagnosis and underreporting; it is estimated that there were approximately 718000 incident gonorrhea cases in 2000 (4). After national implementation of gonorrhea control activities in the 1970s, the incidence of gonorrhea in the United States declined markedly, with a 74% reduction in rates from 1975 to 1997. Although rates have remained relatively stable over the past decade, in 2006 the national gonorrhea case rate (120.9 cases per 100000 population) increased for the second consecutive year, particularly in the western United States (3, 5). Rates of gonorrhea remain high in the South and among African Americans, adolescents, young adults, and men who have sex with men. Recent reports have also documented high rates of gonorrhea among HIV-infected men who have sex with men (3). Because of increased infection rates, high burden of disease, and the reproductive and economic implications of gonorrhea infection, prevention and control of gonorrhea is an important public health concern (6, 7). As current therapeutic options become more limited, we describe the emergent challenges to maintaining antimicrobial effectiveness and a comprehensive approach to gonorrhea control. Historical Perspective on Antimicrobial Resistance An essential element in gonorrhea control is the availability and provision of appropriate, effective antimicrobial therapy. Effective treatment not only eradicates infection in the affected individual and prevents the development of complications, it also has an important public health benefit of shortening the duration of infection, thus decreasing transmission and eliminating reservoirs of infection. However, over the past 60 years N. gonorrhoeae has developed resistance to multiple classes of antimicrobials (Appendix Figure). Sulfanilamides were used for gonococcal treatment after their introduction in 1936, but their efficacy was short-lived because of the rapid emergence of resistance by 1945 (8). Penicillin became the recommended antimicrobial regimen for the next 40 years. The progressive decline in susceptibilityinitially associated with chromosomally mediated resistance (exhibited by a stepwise increase in resistance) and later by the acquisition and spread of plasmids containing genes for penicillinase productionrequired serial increases in the recommended dose of intramuscular procaine penicillin (with probenecid) from 50000 units in 1945 to 4.8 million units by the early 1970s (9). In 1985, because of emerging penicillin resistance, ceftriaxone became a recommended regimen for the treatment of uncomplicated gonococcal infections (10). At the same time, tetracycline resistance (both plasmid and chromosomally mediated) was spreading to the extent that tetracycline was no longer a viable treatment option. By 1989, resistance to penicillin was sufficiently widespread that penicillin was no longer effective. Ceftriaxone then became the recommended regimen for gonorrhea therapy, with ciprofloxacin as an alternative treatment option (11). By 1993, on the basis of data regarding high efficacy, safety, and convenience as single-dose therapies, oral fluoroquinolones (ciprofloxacin, ofloxacin) were recommended as oral regimens for gonorrhea treatment, as was the oral third-generation cephalosporin cefixime (12). Appendix Figure. Historical perspective on antimicrobial resistance in the United States. QRNG = quinolone-resistant Neisseria gonorrhoeae; MSM = men who have sex with men. In 1986, concerns about emerging gonococcal antimicrobial resistance lead to the development of the Gonococcal Isolate Surveillance Project (GISP), a national sentinel surveillance system that monitors antimicrobial susceptibility in the United States. Each year, approximately 6000 urethral gonococcal isolates from men attending 25 to 30 sexually transmitted disease (STD) clinics throughout the country are collected and analyzed to provide national data that help guide treatment recommendations. The GISP findings of notable importance include the continued high prevalence of penicillin and tetracycline resistance, which has remained greater than 15%; the increasing prevalence of isolates with decreased susceptibility to macrolides; the appearance of a limited number of multidrug-resistant isolates with decreased susceptibility to cefixime (3); and most important, the dramatic spread of quinolone-resistant N. gonorrhoeae. Based in part on data from GISP, the emergence of quinolone-resistant N. gonorrhoeae was first identified in Hawaii in 1991, at about same time that it was recognized as a problem in Asia (13). Thereafter, sporadic occurrences of quinolone-resistant N. gonorrhoeae were noted in the United States throughout the 1990s. By 2000, quinolone-resistant N. gonorrhoeae was increasingly observed in persons who became infected in Asia, the Pacific Islands (including Hawaii), or California. As a result, fluoroquinolones were no longer recommended for treating gonorrhea acquired in those locales (14, 15). Over the next several years, GISP identified increased rates of quinolone-resistant N. gonorrhoeae among men who have sex with men. This finding prompted an advisory in 2004 that fluoroquinolones were no longer recommended for treating gonorrhea in men who have sex with men, regardless of locale (16). Most recently, data from GISP indicate that quinolone-resistant N. gonorrhoeae is widely dispersed in the United States and that in 2006 the infection accounted for 39% of gonococcal isolates in men who have sex with men and 7% in heterosexual men. On the basis of these cumulative data, the Centers for Disease Control and Prevention (CDC) announced that fluoroquinolones are no longer recommended for treating gonococcal infections and associated conditions, such as pelvic inflammatory disease or epididymitis, in any population in the United States (17). The antimicrobial resistance data from GISP have provided a rational basis for recommended gonococcal treatment regimens. However, data from this sentinel surveillance system have limitations. The GISP data may not be representative of the total population with gonorrhea in the United States, because the current national surveillance system oversamples West Coast locations (where new resistant strains have been first detected), evaluates only male urethral isolates obtained from STD clinics, and samples only a minority of reported gonococcal infections. Dramatic differences in quinolone-resistant N. gonorrhoeae prevalence by geographic location and sexual orientation illustrate the challenge of achieving accurate representation (18). The rapid spread throughout the United States of quinolone-resistant N. gonorrhoeae in heterosexual men, as well as among men who have sex with men, makes defining remaining pockets of continued susceptibility of N. gonorrhoeae problematic. These limitations highlight the difficulty of defining an appropriate sentinel population and a frequency of sampling with sufficient representation to assure susceptibility in a particular locale. Thus, there is a need to monitor antimicrobial resistance at the local level, which would provide a more in-depth understanding of resistance trends and contribute to decisions that affect treatment recommendations in various locations (19, 20). Evolution of Criteria for Gonorrhea Treatment Recommendations The epidemiology of antimicrobial resistance guides decisions about gonococcal treatment recommendations. As discussed, data from GISP are critical when evaluated along with other relevant data, such as those provided by the Gonococcal Antimicrobial Surveillance Program of the Western Pacific Regional Office of the World Health Organization (WHO) in Southeast Asia and the Pacific region. The CDC and the WHO have recommended a change in the treatment regimen when the prevalence of antimicrobial resistance exceeds 5% for a specific antibiotic, while taking into account the prevalence of gonorrhea in the community, the cost of diagnostic and treatment regimens, and the availability of antimicrobial susceptibility data (2123). An accepted definition of gonococcal treatment efficacy requires a cure rate of over 95% with a lower bound of the 95% CI of at least 90% (24). At the time this criterion was proposed, many antimicrobial regimens met this standard, but in an attempt to reduce the risk for therapeutic failure and development of antimicrobial resistance, more stringent criteria were proposed by Moran and colleagues (25). Their criteria specified that efficacy exceed 95% in summed clinical trials, but required that the lower bound of the 95% CI also be at least 95%. In addition to efficacy data, decisions regarding treatment recommendations involve consideration of other factors. These include administration of at least twice the minimum dose to ensure therapeutic reserve, documentation that susceptibility is not lower among organisms recovered after treatment, and evidence that the serum or plasma concentration with the recommended dose is at least 4 times the minimum inhibitory concentration required to inhibit 90% of strains (MIC90) for 10 hours after the concentration peak (25). These stringent clinical efficacy criteria (95% efficacy with 95% CI) were used to determine the gonorrhea treatment regimens recommended in the CDC STD Treatment Guidelines since 1993. However, it was recently suggested that these criteria be modified, given the propensity of N. gonorrhoeae to develo

Self-reported childhood and adolescent sexual abuse among adult homosexual and bisexual men

From May 1989 through April 1990, 1,001 adult homosexual and bisexual men attending sexually transmitted disease clinics were interviewed regarding potentially abusive sexual contacts during childhood and adolescence. Thirty-seven percent of participants reported they had been encouraged or forced to have sexual contact before age 19 with an older or more powerful partner; 94% occurred with men. Median age of the participant at first contact was 10; median age difference between partners was 11 years. Fifty-one percent involved use of force; 33% involved anal sex. Black and Hispanic men were more likely than white men to report such sexual contact. Using developmentally-based criteria to define sexual abuse, 93% of participants reporting sexual contact with an older or more powerful partner were classified as sexually abused. Our data suggest the risk of sexual abuse may be high among some male youth and increased attention should be devoted to prevention as well as early identification and treatment.

Readiness of high-risk populations in the HIV network for prevention trials to participate in HIV vaccine efficacy trials in the United States

Objective:To determine the willingness of populations at high risk of HIV-1 infection to participate in HIV vaccine efficacy trials, determine factors influencing decision-making, and evaluate knowledge levels of vaccine trial concepts. Design:Cross-sectional study. Methods:HIV-1-negative homosexual men, male and female injecting drug users and non-injecting women at heterosexual risk were recruited in eight cities in the United States (n = 4892). Results:A substantial proportion of the study population (77%) would definitely (27%) or probably (50%) be willing to participate in a randomized vaccine efficacy trial. Increased willingness was associated with high-risk behaviors, lower education level, being uninsured or covered by public insurance, and not having been in a previous vaccine preparedness study. Altruism and a desire for protection from the vaccine were major motivators for participation. Major concerns included positive HIV-1 antibody test due to vaccine, safety of the vaccine, and possible problems with insurance or foreign travel. Baseline knowledge of vaccine trial concepts was low. Conclusions:It is likely that high-risk volunteers will be willing to enroll in HIV vaccine efficacy trials. A variety of participant and community educational strategies are needed to address participant concerns, and to ensure understanding of key concepts prior to giving consent for participation.

High Incidence of New Sexually Transmitted Infections in the Year following a Sexually Transmitted Infection: A Case for Rescreening

Context The Centers for Disease Control and Prevention recommends that women treated for Chlamydia trachomatis infection return in 3 months for evaluation of reinfection. Contribution When data from the RESPECT-2 trial were used, these investigators found that among patients treated for sexually transmitted infections, 25.8% of women and 14.7% of men acquired 1 or more new infections with Chlamydia trachomatis, Neisseria gonorrhoeae, or Trichomonas vaginalis during 1 year of follow-up. Approximately 66% of reinfections were asymptomatic. Implications Successful treatment of incident cases of sexually transmitted infections is unlikely to eliminate a reservoir of infection in the community. Physicians need to perform ongoing surveillance on men and women and encourage lifestyle changes in patients with reinfection. The Editors In 1985, the Centers for Disease Control and Prevention (CDC) treatment guidelines recommended that persons infected with Neisseria gonorrhoeae should return for a test of cure to be sure that the antibiotics had cured the infection (1). With new medications, treatment failure became rare, and by 1989, the guidelines suggested testing 1 to 2 months after treatment to detect treatment failure and reinfection (2). By 1993, the guidelines stated only that a test of cure was not recommended for N. gonorrhoeae (3). Test of cure has been unnecessary for Chlamydia trachomatis after treatment with first-line drugs, but infections detected among women several months after treatment have suggested that rescreening might be effective for detecting reinfection (3). Recent studies have found that 11% to 15% of women treated for C. trachomatis were infected when retested 3 to 4 months after treatment, possibly due to treatment failure, reinfection from an untreated partner, or infection from a new partner (46). New infections are often asymptomatic. One study with scheduled follow-up visits found that 62% of new C. trachomatis infections in men and in women were asymptomatic or unrecognized and would therefore probably be missed without rescreening (7). Untreated C. trachomatis infections can persist for years (8) and put infected women at risk for complications of asymptomatic pelvic inflammatory disease (9). In addition, transmission from asymptomatic persons may be responsible for most new infections in a community (10). The CDC has recommended that health care providers consider advising women with diagnoses of C. trachomatis infection to have another C. trachomatis test in 3 monthsnot as a test of cure but as a test for reinfection (11). We wondered whether men might also benefit from retesting, whether retesting should be expanded to include persons with N. gonorrhoeae or Trichomonas vaginalis infections (12), and whether there were other factors that clinicians could use to recommend retesting. We analyzed data from a large prevention counseling trial (13) that included baseline and 4 scheduled follow-up visits of patients in 3 sexually transmitted disease (STD) clinics to determine the incidence of new sexually transmitted infections during the year after a visit to the clinics. Methods A multicenter randomized, controlled trial of HIV prevention counseling with a rapid HIV test or a standard HIV test (RESPECT-2) was conducted in 3 public STD clinics in Denver, Colorado; Long Beach, California; and Newark, New Jersey. Primary analyses and detailed methods are described elsewhere (13). Briefly, eligible clients were those who came to the clinics for a full diagnostic examination for sexually transmitted infections, were HIV-negative at enrollment, reported having vaginal or anal sex in the preceding 3 months, and were 15 to 39 years of age. At the initial visit, participants were counseled, examined, and tested for sexually transmitted infections and HIV infection. Outcomes were measured at 13-week intervals, scheduled 3, 6, 9, and 12 months from the date of enrollment. Before each follow-up visit, study staff mailed a reminder letter to each participant and made a reminder telephone call. When participants did not keep appointments, staff mailed additional reminder letters and made additional telephone calls to reschedule the visit as needed. Participants who were due for a study follow-up visit were screened for sexually transmitted infections and were interviewed if they visited the clinic any time from 1 week before the due date up to 12 weeks after the due date. Participants were given

The relationship between condom use and herpes simplex virus acquisition

25 for completing each follow-up visit. This amount was later increased to

Incidence and repeat infection rates of Chlamydia trachomatis among male and female patients in an STD clinic: implications for screening and rescreening.

50 in an attempt to improve retention rates. Participants were tested for C. trachomatis, N. gonorrhoeae, and T. vaginalis infections at enrollment, at each quarterly follow-up visit, and at other visits not related to the study that occurred during the 12-month follow-up period (interim visits). An incident sexually transmitted infection was defined as a positive laboratory result either preceded by a negative result for the same infection or detected more than 14 days after provision of antibiotics effective against that infection. Testing was done in the local laboratories used by each clinic. Tests for C. trachomatis and N. gonorrhoeae infections were done on urine specimens by using nucleic acid amplification tests. The sensitivity and specificity values from the package inserts for these tests are cited here; the exact values are difficult to establish because there is no gold standard for identifying infected patients (14). The Long Beach and Newark clinics used ligase chain reaction (LCx Uriprobe, Abbott Diagnostics Division, Abbott Park, Illinois); the sensitivity and specificity for C. trachomatis were 93.1% and 97.1%, respectively, and the sensitivity and specificity for N. gonorrhoeae were 97.5% and 98.3%, respectively (15, 16). The Denver clinic used polymerase chain reaction initially (Cobas Amplicor, Roche Diagnostic Systems, Inc., Branchburg, New Jersey); the sensitivity and specificity for C. trachomatis were 93.4% and 96.7%, respectively, and the sensitivity and specificity for N. gonorrhoeae were 97.1% and 98.1%, respectively (17, 18). Eighteen months later, however, this clinic changed to using strand displacement amplification (BDProbeTec ET, BD Diagnostic Systems, Sparks, Maryland); the sensitivity and specificity for C. trachomatis were 90.7% and 96.6%, respectively, and the sensitivity and specificity for N. gonorrhoeae were 96.0% and 98.8%, respectively) (19). Trichomonas vaginalis was cultured by using the InPouch TV test (BioMed Diagnostics Inc., San Jose, California) or modified Diamond medium as the culture medium. The sensitivity has been estimated at 82.4% for the InPouch TV test and 87.8% for Diamond medium; specificity for both culture methods is nearly 100% (20). Cultures were done by using vaginal swab specimens from women. At follow-up visits, vaginal swabs were collected by the participant (Denver and Long Beach) or by a clinician (Newark), depending on local clinic policy. Behavioral data were collected by using Audio Computer-Assisted Self-Interview technology at enrollment and at each scheduled study follow-up visit. For most questions, a uniform 3-month recall period was used, regardless of the time since the most recent study visit. Because previous work has shown that most new infections are asymptomatic, we limited our analysis to participants who returned for testing and therefore could be classified as infected or not infected. Return visits with testing and interviews were scheduled every 3 months, and most participants returned within 2 weeks of their scheduled time. However, some participants also returned before their scheduled visit because of concern about a possible infection. Those who returned early were tested for sexually transmitted infections and were told to return for their scheduled visit for the interview and repeated testing. All test results from interim visits between 2 interviews were associated with behaviors reported during the next scheduled interview after the interim tests. Study interviews were conducted the first time the participant returned during the scheduled follow-up time (visit 1, 84 to 174 days; visit 2, 175 to 265 days; visit 3, 266 to 356 days; and visit 4, 357 to 448 days). Test data from participants who missed interviews were grouped in the analysis with their next interview. We excluded data from visits that occurred after participants missed 2 consecutive follow-up interviews. Men who reported having sex with men in the baseline interview were also excluded because of the small sample size. Person-years at risk were calculated by using the time between interviews. Participants could contribute up to 4 intervals of observation. Those who had multiple infections with the same organism in the same interval were only counted as having 1 infection, but if an infection recurred in a different interval it was counted again. We looked for 2 types of risk factors for infection. First, we looked for characteristics that clinicians could identify during a clinic visit that might predict infection at a subsequent visit. These factors included demographic characteristics, past risk behaviors, and infections detected during that visit. Second, we looked at events that might occur during follow-up that would alert patients to a need to return for testing for sexually transmitted infections. These factors included acquiring a new partner or having sex with more than 1 partner. Multivariate analysis of factors associated with sexually transmitted infection included serial measures for each participant. We performed unconditional logistic regression using generalized estimating equations, which accounted for within-participant correlations of repeated measures (21). Because this method assumes that missing data are missing completely at random, we assessed the relationship between missing visits and response variables for all 2419 participants included in our stu